Human secreted proteins

ABSTRACT

The present invention relates to human secreted polypeptides, and isolated nucleic acid molecules encoding said polypeptides, useful for diagnosing and treating hematopoietic and hematologic diseases, disorders, and/or conditions related thereto. Antibodies that bind these polypeptides are also encompassed by the present invention. Also encompassed by the invention are vectors, host cells, and recombinant and synthetic methods for producing said polynucleotides, polypeptides, and/or antibodies. The invention further encompasses screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further encompasses methods and compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

FIELD OF THE INVENTION

The present invention relates to human secreted proteins/polypeptides, and isolated nucleic acid molecules encoding said proteins/polypeptides, useful for detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders. Antibodies that bind these polypeptides are also encompassed by the present invention. Also encompassed by the invention are vectors, host cells, and recombinant and synthetic methods for producing said polynucleotides, polypeptides, and/or antibodies. The invention further encompasses screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further encompasses methods and compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

BACKGROUND OF THE INVENTION

Blood is composed of a fluid component, plasma, in which are suspended red blood cells, white blood cells, and platelets. This suspension, circulating through the cardiovascular system, forms the basis of the immune system, provides all of the body's tissues with oxygen and nutrients, and removes carbon dioxide and other metabolic byproducts for excretion.

Immune cells, red blood cells, and platelets, are derived from common precursor stem cells and develop through a process known as hematopoiesis. During fetal life hematopoiesis occurs in the liver and spleen, but in the adult, hematopoiesis occurs primarily in the bone marrow and thymus. The stem cells from which all blood cells are derived proliferate and differentiate into the various blood cell lineages, (e.g., lymphoid cells (B or T cells), myeloid cells (basophils, eosinophils, neutrophils, macrophages, mast cells), thrombocytes (platelets), or erythrocytes (red blood cells)) in response to cytokines and other signals received from cells (e.g., stromal cells) in the bone marrow microenvironment. Many of the cytokines that promote the growth and differentiation of hematopoietic stem cells are known as “colony stimulating factors”. For example, interleukin-3 (IL-3, and also known as multi-colony stimulating factor) and granulocyte macrophage colony stimulating factor (GM-CSF), which are released by activated macrophages and T cells, stimulate the production of macrophages and granulocytes (myelopoiesis). Stem cell factor (SCF, c-kit ligand) is a growth factor for primitive lymphoid and myeloid hematopoietic bone marrow progenitor cells expressing the early cell surface marker CD34. Other hematopoietic cytokines/growth factors include, but are not limited to macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), and erythropoietin (EPO). Interleukins-1, 6, and 7 have also been shown to function as hematopoietic growth factors/cytokines. Deficiencies in the quantities of mature red or white blood cells, either as a result of insufficient production or excessive destruction, may result in anemias and/or immunodeficiencies.

In addition to the cellular component of the blood, there are a remarkable variety of soluble blood-borne proteins that serve important physiological functions. Descriptions of some of the functional classes of blood proteins, along with representative members of these classes, are given below.

Coagulation Factors

The formation of insoluble protein aggregates at the site of vascular injury or inflammation, termed coagulation, is the result of multiple interacting coagulation factors (Dahlback, B., Lancet 355:1627-32). This cascade of interdependent proteins (including Factors V, VIII, IX, X XI, and XII) results in the production of the protease, thrombin. Thrombin converts blood-soluble fibrinogen into fibrin, which polymerizes into insoluble clots that are stabilized by the activity of Factor XIII. This process is balanced by the activity of coagulation inhibitors such as antithrombin III, heparin cofactor II, Protein C and Protein S. Imbalance between pro-clotting factors and coagulation inhibitors leads to potentially serious medical conditions, including improper wound healing and the bleeding disorders hemophilia A and B, as well as excessive clotting disorders such as thrombosis (e.g. cerebral, coronary, and placental), pulmonary embolus, stroke, and coronary artery disease. For a more extensive review see Triplett, D., Clin Chem 46:1260-9.

Immunoproteins

Blood plasma contains a number of proteins that contribute to the immune response. Immunoglobulin antibodies are glycoproteins with similar structural domains, which bind to specific antigenic invaders and trigger other components of the immune system. The complement cascade, a network of about 20 interacting proteins, is activated by antigen-antibody complexes and results in the lysis of infected cells, as well as other important immune functions. Immunoproteins are important tools for the diagnosis and treatment of infection, cancer, and other disorders. For more detailed discussion of immunoproteins see Meri, J. and Jarva, H., Vox Sang 74 suppl. 2:291-302 and Chapter 23 of Molecular Biology of the Cell, 3^(rd) Edition, edited by Alberts, B. et al.

Hormones

The blood serves as a major vehicle for hormones and other secreted signaling molecules that act at a site distant to their release. A number of peptide hormones function as regulators of homeostatic processes. For example, parathyroid hormone and calcitonin oppositely regulate serum levels of calcium. Blood-borne peptide hormones that regulate carbohydrate metabolism include insulin, glucagon, and adrenocorticotropin hormone. Vasopressin, angiotensin, and bradykinin are hormones that modulate vasodilation and blood pressure. Follicle-stimulating hormone and leutinizing hormone play important roles in both male and female reproductive functions. Dysfunction of these hormones can lead to a wide spectrum of disorders, including osteoporosis, diabetes, psychiatric disorders, hypoglycemia, obesity, infertility, as well as hypo- and hypertension.

Cytokines

Cytokines are a class of circulating proteins that act primarily as intercellular signaling molecules regulating hematopoiesis, angiogenesis, and immune system functions. One subgroup of cytokines, the hematopoietins, regulates hematopoietic stem cell differentiation to maintain the proper number and proportions of each blood cell type. For example, the production of erythrocytes is stimulated by the release of erythropoietin from the kidneys in response to decreased blood oxygen levels. Similarly, thrombopoietin stimulates the proliferation and differentiation of megakaryocytes, leading to increased platelet production. Another cytokine subgroup, the chemokines, is secreted by cells of the immune system, and act to coordinate the immune response to an invading antigen. This is a large and diverse class of proteins, and includes RANTES, eotaxin, lymphotactin, MIP-1, and the interleukins. Many of these polypeptides have uses in the diagnosis and treatment of immunological disorders and infection (Holldack. J. et al., Med Ped Oncol Suppl 2:2-9; Chapter 23, Immunology, edited by Elgert, K.).

Carrier Proteins

A number of soluble proteins found in blood function as carriers of other molecules such as nutrients and waste products. Carrier proteins can also bind exogenously delivered drugs and influence pharmacokinetic properties such as serum half-life and tissue adsorption. Serum albumin, comprising about half of the protein found in blood plasma, regulates osmotic pressure of blood, as well as binds many bioactive molecules. Transferrin is a blood carrier protein that regulates iron levels, while ceruloplasmin regulates copper levels. Thus there exists a clear need for novel polynucleotides and polypeptides (as well as antibodies, agonists, and antagonists) useful in diagnostic and therapeutic methods for detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders; such as, for example, leukemias, lymphomas, hemophilias, anemias, immunodeficiency disorders (including AIDS), amongst many other conditions. See, e.g., “Blood Related Disorders” and “Immune Activity” sections, infra.

SUMMARY OF THE INVENTION

The present invention encompasses human secreted proteins/polypeptides, and isolated nucleic acid molecules encoding said proteins/polypeptides, useful for detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoeitic and hematololgic disorders and diseases. Antibodies that bind these polypeptides are also encompassed by the present invention; as are vectors, host cells, and recombinant and synthetic methods for producing said polynucleotides, polypeptides, and/or antibodies. The invention further encompasses screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention also encompasses methods and compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

DETAILED DESCRIPTION

Polynucleotides and Polypeptides of the Invention

Description of Table 1A

Table 1A summarizes information concerning certain polypnucleotides and polypeptides of the invention. The first column provides the gene number in the application for each clone identifier. The second column provides a unique clone identifier, “Clone ID:”, for a cDNA clone related to each contig sequence disclosed in Table 1A. Third column, the cDNA Clones identified in the second column were deposited as indicated in the third column (i.e. by ATCC Deposit No:Z and deposit date). Some of the deposits contain multiple different clones corresponding to the same gene. In the fourth column, “Vector” refers to the type of vector contained in the corresponding cDNA Clone identified in the second column. In the fifth column, the nucleotide sequence identified as “NT SEQ ID NO:X” was assembled from partially homologous (“overlapping”) sequences obtained from the corresponding cDNA clone identified in the second column and, in some cases, from additional related cDNA clones. The overlapping sequences were assembled into a single contiguous sequence of high redundancy (usually three to five overlapping sequences at each nucleotide position), resulting in a final sequence identified as SEQ ID NO:X. In the sixth column, “Total NT Seq.” refers to the total number of nucleotides in the contig sequence identified as SEQ ID NO:X.” The deposited clone may contain all or most of these sequences, reflected by the nucleotide position indicated as “5′ NT of Clone Seq.” (seventh column) and the “3′ NT of Clone Seq.” (eighth column) of SEQ ID NO:X. In the ninth column, the nucleotide position of SEQ ID NO:X of the putative start codon (methionine) is identified as “5′ NT of Start Codon.” Similarly, in column ten, the nucleotide position of SEQ ID NO:X of the predicted signal sequence is identified as “5′ NT of First AA of Signal Pep.” In the eleventh column, the translated amino acid sequence, beginning with the methionine, is identified as “AA SEQ ID NO:Y,” although other reading frames can also be routinely translated using known molecular biology techniques. The polypeptides produced by these alternative open reading frames are specifically contemplated by the present invention.

In the twelfth and thirteenth columns of Table 1A, the first and last amino acid position of SEQ ID NO:Y of the predicted signal peptide is identified as “First AA of Sig Pep” and “Last AA of Sig Pep.” In the fourteenth column, the predicted first amino acid position of SEQ ID NO:Y of the secreted portion is identified as “Predicted First AA of Secreted Portion”. The amino acid position of SEQ ID NO:Y of the last amino acid encoded by the open reading frame is identified in the fifteenth column as “Last AA of ORF”.

SEQ ID NO:X (where X may be any of the polynucleotide sequences disclosed in the sequence listing) and the translated SEQ ID NO:Y (where Y may be any of the polypeptide sequences disclosed in the sequence listing) are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, SEQ ID NO:X is useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA contained in the deposited clone. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ ID NO:Y may be used, for example, to generate antibodies which bind specifically to proteins containing the polypeptides and the secreted proteins encoded by the cDNA clones identified in Table 1A and/or elsewhere herein.

Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).

Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X, and the predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of the invention deposited with the ATCC, as set forth in Table 1A. The nucleotide sequence of each deposited plasmid can readily be determined by sequencing the deposited plasmid in accordance with known methods.

The predicted amino acid sequence can then be verified from such deposits. Moreover, the amino acid sequence of the protein encoded by a particular plasmid can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence.

Also provided in Table 1A is the name of the vector which contains the cDNA plasmid. Each vector is routinely used in the art. The following additional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector. Both phagemids may be transformed into E. coli strain XL-1 Blue, also available from StratageneVectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59 (1993). Vector lafmid BA (Bento Soares, Columbia University, New York, N.Y.) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR®2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ ID NO:X, SEQ ID NO:Y, and/or a deposited cDNA (cDNA Clone ID). The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include, but are not limited to, preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.

Also provided in the present invention are allelic variants, orthologs, and/or species homologs. Procedures known in the art can be used to obtain full-length genes, allelic variants, splice variants, full-length coding portions, orthologs, and/or species homologs of genes corresponding to SEQ ID NO:X and SEQ ID NO:Y using information from the sequences disclosed herein or the clones deposited with the ATCC. For example, allelic variants and/or species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for allelic variants and/or the desired homologue.

The present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ID NO:X and/or a cDNA contained in ATCC Deposit No. Z. The present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X, and/or a polypeptide encoded by a cDNA contained in ATCC deposit No. Z. Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by the cDNA contained in ATCC Deposit No. Z, are also encompassed by the invention. The present invention further encompasses a polynucleotide comprising, or alternatively consisting of the complement of the nucleic acid sequence of SEQ ID NO:X, and/or the complement of the coding strand of the cDNA contained in ATCC Deposit No. Z.

Description of Table 1B (Comprised of Tables 1B.1 and 1B.2)

Table 1B.1 and Table 1B.2 summarize some of the polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID:), contig sequences (contig identifier (Contig ID:) and contig nucleotide sequence identifiers (SEQ ID NO:X)) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby. The first column of Tables 1B.1 and 1B.2 provide the gene numbers in the application for each clone identifier. The second column of Tables 1B.1 and 1B.2 provide unique clone identifiers, “Clone ID:”, for cDNA clones related to each contig sequence disclosed in Table 1A and/or Table 1B. The third column of Tables 1B.1 and 1B.2 provide unique contig identifiers, “Contig ID:” for each of the contig sequences disclosed in these tables. The fourth column of Tables 1B.1 and 1B.2 provide the sequence identifiers, “SEQ ID NO:X”, for each of the contig sequences disclosed in Table 1A and/or 1B.

Table 1B.1

The fifth column of Table 1B.1, “ORF (From-To)”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:X that delineates the preferred open reading frame (ORF) that encodes the amino acid sequence shown in the sequence listing and referenced in Table 1B.1 as SEQ ID NO:Y (column 6). Column 7 of Table 1B.1 lists residues comprising predicted epitopes contained in the polypeptides encoded by each of the preferred ORFs (SEQ ID NO:Y). Identification of potential immunogenic regions was performed according to the method of Jameson and Wolf (CABIOS, 4; 181-186 (1988)); specifically, the Genetics Computer Group (GCG) implementation of this algorithm, embodied in the program PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group (GCG), Madison, Wis.). This method returns a measure of the probability that a given residue is found on the surface of the protein. Regions where the antigenic index score is greater than 0.9 over at least 6 amino acids are indicated in Table 1B.1 as “Predicted Epitopes”. In particular embodiments, polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table 1B.1. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly. Column 8 of Table 1B.1 (“Cytologic Band”) provides the chromosomal location of polynucleotides corresponding to SEQ ID NO:X. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Given a presumptive chromosomal location, disease locus association was determined by comparison with the Morbid Map, derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM™. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). If the putative chromosomal location of the Query overlaps with the chromosomal location of a Morbid Map entry, an OMIM identification number is disclosed in Table 1B.1, column 9 labeled “OMIM Disease Reference(s)”. A key to the OMIM reference identification numbers is provided in Table 5.

Table 1B.2

Column 5 of Table 1B.2, “Tissue Distribution” shows the expression profile of tissue, cells, and/or cell line libraries which express the polynucleotides of the invention. The first code number shown in Table 1B.2 column 5 (preceding the colon), represents the tissue/cell source identifier code corresponding to the key provided in Table 4. Expression of these polynucleotides was not observed in the other tissues and/or cell libraries tested. The second number in column 5 (following the colon), represents the number of times a sequence corresponding to the reference polynucleotide sequence (e.g., SEQ ID NO:X) was identified in the corresponding tissue/cell source. Those tissue/cell source identifier codes in which the first two letters are “AR” designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of ³³P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after “[array code]:” represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissue(s) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression.

Description of Table 1C

Table 1C summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID:), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ ID NO:B). The first column provides a unique clone identifier, “Clone ID:”, for a cDNA clone related to each contig sequence. The second column provides the sequence identifier, “SEQ ID NO:X”, for each contig sequence. The third column provides a unique contig identifier, “Contig ID:” for each contig sequence. The fourth column, provides a BAC identifier “BAC ID NO:A” for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, “SEQ ID NO:B” for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, “Exon From-To”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).

Description of Table 1D

Table 1D: In preferred embodiments, the present invention encompasses a method of detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders; comprising administering to a patient in which such treatment, prevention, or amelioration is desired a protein, nucleic acid, or antibody of the invention (or fragment or variant thereof) represented by Table 1A, Table 1B, and Table 1C, in an amount effective to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate the disease or disorder.

As indicated in Table 1D, the polynucleotides, polypeptides, agonists, or antagonists of the present invention (including antibodies) can be used in assays to test for one or more biological activities. If these polynucleotides and polypeptides do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity. Thus, the polynucleotides or polypeptides, or agonists or antagonists thereof (including antibodies) could be used to treat the associated disease.

Table 1D provides information related to biological activities for polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof). Table 1D also provides information related to assays which may be used to test polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof) for the corresponding biological activities. The first column (“Gene No.”) provides the gene number in the application for each clone identifier. The second column (“cDNA Clone ID:”) provides the unique clone identifier for each clone as previously described and indicated in Tables 1A, 1B, and 1C. The third column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ ID Number for polypeptide sequences encoded by the corresponding cDNA clones (also as indicated in Tables 1A, 1B, and 2). The fourth column (“Biological Activity”) indicates a biological activity corresponding to the indicated polypeptides (or polynucleotides encoding said polypeptides). The fifth column (“Exemplary Activity Assay”) further describes the corresponding biological activity and provides information pertaining to the various types of assays which may be performed to test, demonstrate, or quantify the corresponding biological activity. Table 1D describes the use of FMAT technology, inter alia, for testing or demonstrating various biological activities. Fluorometric microvolume assay technology (FMAT) is a fluorescence-based system which provides a means to perform nonradioactive cell- and bead-based assays to detect activation of cell signal transduction pathways. This technology was designed specifically for ligand binding and immunological assays. Using this technology, fluorescent cells or beads at the bottom of the well are detected as localized areas of concentrated fluorescence using a data processing system. Unbound flurophore comprising the background signal is ignored, allowing for a wide variety of homogeneous assays. FMAT technology may be used for peptide ligand binding assays, immunofluorescence, apoptosis, cytotoxicity, and bead-based immunocapture assays. See, Miraglia S et. al., “Homogeneous cell and bead based assays for highthroughput screening using flourometric microvolume assay technology,” Journal of Biomolecular Screening; 4:193-204 (1999). In particular, FMAT technology may be used to test, confirm and/or identify the ability of polypeptides (including polypeptide fragments and variants) to activate signal transduction pathways. For example, FMAT technology may be used to test, confirm, and/or identify the ability of polypeptides to upregulate production of immunomodulatory proteins (such as, for example, interleulins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as other cellular regulators (e.g. insulin)).

Table 1D also describes the use of kinase assays for testing, demonstrating, or quantifying biological activity. In this regard, the phosphorylation and de-phosphorylation of specific amino acid residues (e.g. Tyrosine, Serine, Threonine) on cell-signal transduction proteins provides a fast, reversible means for activation and de-activation of cellular signal transduction pathways. Moreover, cell signal transduction via phosphorylation/de-phosphorylation is crucial to the regulation of a wide variety of cellular processes (e.g. proliferation, differentiation, migration, apoptosis, etc.). Accordingly, kinase assays provide a powerful tool useful for testing, confirming, and/or identifying polypeptides (including polypeptide fragments and variants) that mediate cell signal transduction events via protein phosphorylation. See e.g., Forrer, P., Tamaskovic R., and Jaussi, R. “Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and p38 Kinase Activities” Biol. Chem. 379(8-9): 1101-1110 (1998).

Description of Table 2

Table 2 summarizes homology and features of some of the polypeptides of the invention. The first column provides a unique clone identifier, “Clone ID:”, corresponding to a cDNA clone disclosed in Table 1A or Table 1B. The second column provides the unique contig identifier, “Contig ID:” corresponding to contigs in Table 1B and allowing for correlation with the information in Table 1B. The third column provides the sequence identifier, “SEQ ID NO:X”, for the contig polynucleotide sequence. The fourth column provides the analysis method by which the homology/identity disclosed in the Table was determined. Comparisons were made between polypeptides encoded by the polynucleotides of the invention and either a non-redundant protein database (herein referred to as “NR”), or a database of protein families (herein referred to as “PFAM”) as further described below. The fifth column provides a description of the PFAM/NR hit having a significant match to a polypeptide of the invention. Column six provides the accession number of the PFAM/NR hit disclosed in the fifth column. Column seven, “Score/Percent Identity”, provides a quality score or the percent identity, of the hit disclosed in columns five and six. Columns 8 and 9, “NT From” and “NT To” respectively, delineate the polynucleotides in “SEQ ID NO:X” that encode a polypeptide having a significant match to the PFAM/NR database as disclosed in the fifth and sixth columns. In specific embodiments polypeptides of the invention comprise, or alternatively consist of, an amino acid sequence encoded by a polynucleotide in SEQ ID NO:X as delineated in columns 8 and 9, or fragments or variants thereof.

Description of Table 3

Table 3 provides polynucleotide sequences that may be disclaimed according to certain embodiments of the invention. The first column provides a unique clone identifier, “Clone ID”, for a cDNA clone related to contig sequences disclosed in Table 1B. The second column provides the sequence identifier, “SEQ ID NO:X”, for contig sequences disclosed in Table 1A and/or Table 1B. The third column provides the unique contig identifier, “Contig ID:”, for contigs disclosed in Table 1B. The fourth column provides a unique integer ‘a’ where ‘a’ is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO:X, and the fifth column provides a unique integer ‘b’ where ‘b’ is any integer between 15 and the final nucleotide of SEQ ID NO:X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a +14. For each of the polynucleotides shown as SEQ ID NO:X, the uniquely defined integers can be substituted into the general formula of a-b, and used to describe polynucleotides which may be preferably excluded from the invention. In certain embodiments, preferably excluded from the invention are at least one, two, three, four, five, ten, or more of the polynucleotide sequence(s) having the accession number(s) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone).

Description of Table 4

Table 4 provides a key to the tissue/cell source identifier code disclosed in Table 1B.2, column 5. Column 1 of Table 4 provides the tissue/cell source identifier code disclosed in Table 1B.2, Column 5. Columns 2-5 provide a description of the tissue or cell source. Note that “Description” and “Tissue” sources (i.e. columns 2 and 3) having the prefix “a_” indicates organs, tissues, or cells derived from “adult” sources. Codes corresponding to diseased tissues are indicated in column 6 with the word “disease.” The use of the word “disease” in column 6 is non-limiting. The tissue or cell source may be specific (e.g. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ). Furthermore, tissues and/or cells lacking the “diseas” designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder. In numerous cases where the tissue/cell source is a library, column 7 identifies the vector used to generate the library.

Description of Table 5

Table 5 provides a key to the OMIM reference identification numbers disclosed in Table 1B.1, column 9. OMIM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseases associated with the cytologic band disclosed in Table 1B.1, column 8, as determined using the Morbid Map database.

Description of Table 6

Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application. These deposits were made in addition to those described in the Table 1A.

Description of Table 7

Table 7 shows the cDNA libraries sequenced, and ATCC designation numbers and vector information relating to these cDNA libraries. The first column shows the first four letters indicating the Library from which each library clone was derived. The second column indicates the catalogued tissue description for the corresponding libraries. The third column indicates the vector containing the corresponding clones. The fourth column shows the ATCC deposit designation for each libray clone as indicated by the deposit information in Table 6.

Definitions

The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

In the present invention, “isolated” refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered “by the hand of man” from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be “isolated” because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide. The term “isolated” does not refer to genomic or cDNA libraries, whole cell total or mRNA preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic DNA preparations or other compositions where the art demonstrates no distinguishing features of the polynucleotide/sequences of the present invention.

In the present invention, a “secreted” protein refers to those proteins capable of being directed to the ER, secretory vesicles, or the extracellular space as a result of a signal sequence, as well as those proteins released into the extracellular space without necessarily containing a signal sequence. If the secreted protein is released into the extracellular space, the secreted protein can undergo extracellular processing to produce a “mature” protein. Release into the extracellular space can occur by many mechanisms, including exocytosis and proteolytic cleavage.

As used herein, a “polynucleotide” refers to a molecule having a nucleic acid sequence encoding SEQ ID NO:Y or a fragment or variant thereof (e.g., the polypeptide delinated in columns fourteen and fifteen of Table 1A); a nucleic acid sequence contained in SEQ ID NO:X (as described in column 5 of Table 1A and/or column 3 of Table 1B) or the complement thereof; a cDNA sequence contained in Clone ID: (as described in column 2 of Table 1A and/or Table 1B and contained within a library deposited with the ATCC); a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 (EXON From-To) of Table 1C or a fragment or variant thereof; or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1C or the complement thereof. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5′ and 3′ untranslated sequences, the coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence. Moreover, as used herein, a “polypeptide” refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA).

In the present invention, “SEQ ID NO:X” was often generated by overlapping sequences contained in multiple clones (contig analysis). A representative clone containing all or most of the sequence for SEQ ID NO:X is deposited at Human Genome Sciences, Inc. (HGS) in a catalogued and archived library. As shown, for example, in column 2 of Table 1B, each clone is identified by a cDNA Clone ID (identifier generally referred to herein as Clone ID:). Each Clone ID is unique to an individual clone and the Clone ID is all the information needed to retrieve a given clone from the HGS library. Table 7 provides a list of the deposited cDNA libraries. One can use the Clone ID: to determine the library source by reference to Tables 6 and 7. Table 7 lists the deposited cDNA libraries by name and links each library to an ATCC Deposit. Library names contain four characters, for example, “HTWE.” The name of a cDNA clone (Clone ID) isolated from that library begins with the same four characters, for example “HTWEP07”. As mentioned below, Table 1A and/or Table 1B correlates the Clone ID names with SEQ ID NO:X. Thus, starting with an SEQ ID NO:X, one can use Tables 1A, 1B, 6, 7, and 9 to determine the corresponding Clone ID, which library it came from and which ATCC deposit the library is contained in. Furthermore, it is possible to retrieve a given cDNA clone from the source library by techniques known in the art and described elsewhere herein. The ATCC is located at 10801 University Boulevard, Manassas, Va. 20110-2209, USA. The ATCC deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.

In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).

A “polynucleotide” of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO:X, or the complement thereof (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments described herein), the polynucleotide sequence delineated in columns 7 and 8 of Table 1A or the complement thereof, the polynucleotide sequence delineated in columns 8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained in Clone ID: (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments, or the cDNA clone within the pool of cDNA clones deposited with the ATCC, described herein), and/or the polynucleotide sequence delineated in column 6 of Table 1C or the complement thereof. “Stringent hybridization conditions” refers to an overnight incubation at 42 degree C. in a solution comprising 50% formamide, 5×SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5× Denhardt's solution, 10% dextran sulfate, and 20 μg/l ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1×SSC at about 65 degree C.

Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions. Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature. For example, lower stringency conditions include an overnight incubation at 37 degree C. in a solution comprising 6×SSPE (20×SSPE=3M NaCl; 0.2M NaH₂PO₄; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm blocking DNA; followed by washes at 50 degree C. with 1×SSPE, 0.1% SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5×SSC). Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.

Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as any 3′ terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of “polynucleotide,” since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone generated using oligo dT as a primer).

The polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, the polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A polynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. “Modified” bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA and RNA; thus, “polynucleotide” embraces chemically, enzymatically, or metabolically modified forms.

In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).

“SEQ ID NO:X” refers to a polynucleotide sequence described in column 5 of Table 1A, while “SEQ ID NO:Y” refers to a polypeptide sequence described in column 10 of Table 1A. SEQ ID NO:X is identified by an integer specified in column 6 of Table 1A. The polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ID NO:X. The polynucleotide sequences are shown in the sequence listing immediately followed by all of the polypeptide sequences. Thus, a polypeptide sequence corresponding to polynucleotide sequence SEQ ID NO:2 is the first polypeptide sequence shown in the sequence listing. The second polypeptide sequence corresponds to the polynucleotide sequence shown as SEQ ID NO:3, and so on.

The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids. The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W.H. Freeman and Company, New York (1993); POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

“SEQ ID NO:X” refers to a polynucleotide sequence described, for example, in Tables 1A, Table 1B, or Table 2, while “SEQ ID NO:Y” refers to a polypeptide sequence described in column 11 of Table 1A and or column 6 of Table. 1B.1, SEQ ID NO:X is identified by an integer specified in column 4 of Table 1B. The polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ID NO:X. “Clone ID:” refers to a cDNA clone described in column 2 of Table 1A and/or 1B.

“A polypeptide having functional activity” refers to a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) protein. Such functional activities include, but are not limited to, biological activity (e.g. activity useful in treating, preventing and/or ameliorating hematopoietic and hematologic diseases and disorders), antigenicity (ability to bind [or compete with a polypeptide for binding] to an anti-polypeptide antibody), immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide.

The polypeptides of the invention can be assayed for functional activity (e.g. biological activity) using or routinely modifying assays known in the art, as well as assays described herein. Specifically, one of skill in the art may routinely assay secreted polypeptides (including fragments and variants) of the invention for activity using assays as described in the examples section below.

“A polypeptide having biological activity” refers to a polypeptide exhibiting activity similar to, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).

Tables

Table 1A

Table 1A summarizes information concerning certain polypnucleotides and polypeptides of the invention. The first column provides the gene number in the application for each clone identifier. The second column provides a unique clone identifier, “Clone ID:”, for a cDNA clone related to each contig sequence disclosed in Table 1A. Third column, the cDNA Clones identified in the second column were deposited as indicated in the third column (i.e. by ATCC Deposit No:Z and deposit date). Some of the deposits contain multiple different clones corresponding to the same gene. In the fourth column, “Vector” refers to the type of vector contained in the corresponding cDNA Clone identified in the second column. In the fifth column, the nucleotide sequence identified as “NT SEQ ID NO:X” was assembled from partially homologous (“overlapping”) sequences obtained from the corresponding cDNA clone identified in the second column and, in some cases, from additional related cDNA clones. The overlapping sequences were assembled into a single contiguous sequence of high redundancy (usually three to five overlapping sequences at each nucleotide position), resulting in a final sequence identified as SEQ ID NO:X. In the sixth column, “Total NT Seq.” refers to the total number of nucleotides in the contig sequence identified as SEQ ID NO:X.” The deposited clone may contain all or most of these sequences, reflected by the nucleotide position indicated as “5′ NT of Clone Seq.” (seventh column) and the “3′ NT of Clone Seq.” (eighth column) of SEQ ID NO:X. In the ninth column, the nucleotide position of SEQ ID NO:X of the putative start codon (methionine) is identified as “5′ NT of Start Codon.” Similarly, in column ten, the nucleotide position of SEQ ID NO:X of the predicted signal sequence is identified as “5′ NT of First AA of Signal Pep.” In the eleventh column, the translated amino acid sequence, beginning with the methionine, is identified as “AA SEQ ID NO:Y,” although other reading frames can also be routinely translated using known molecular biology techniques. The polypeptides produced by these alternative open reading frames are specifically contemplated by the present invention.

In the twelfth and thirteenth columns of Table 1A, the first and last amino acid position of SEQ ID NO:Y of the predicted signal peptide is identified as “First AA of Sig Pep” and “Last AA of Sig Pep.” In the fourteenth column, the predicted first amino acid position of SEQ ID NO:Y of the secreted portion is identified as “Predicted First AA of Secreted Portion”. The amino acid position of SEQ ID NO:Y of the last amino acid encoded by the open reading frame is identified in the fifteenth column as “Last AA of ORF”.

SEQ ID NO:X (where X may be any of the polynucleotide sequences disclosed in the sequence listing) and the translated SEQ ID NO:Y (where Y may be any of the polypeptide sequences disclosed in the sequence listing) are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, SEQ ID NO:X is useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA contained in the deposited clone. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ ID NO:Y may be used, for example, to generate antibodies which bind specifically to proteins containing the polypeptides and the secreted proteins encoded by the cDNA clones identified in Table 1A and/or elsewhere herein.

Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).

Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X, and the predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of the invention deposited with the ATCC, as set forth in Table 1A. The nucleotide sequence of each deposited plasmid can readily be determined by sequencing the deposited plasmid in accordance with known methods.

The predicted amino acid sequence can then be verified from such deposits. Moreover, the amino acid sequence of the protein encoded by a particular plasmid can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence.

Also provided in Table 1A is the name of the vector which contains the cDNA plasmid. Each vector is routinely used in the art. The following additional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector. Both phagemids may be transformed into E. coli strain XL-1 Blue, also available from Stratagene.

Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59 (1993). Vector lafmid BA (Bento Soares, Columbia University, New York, N.Y.) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR®2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ ID NO:X, SEQ ID NO:Y, and/or a deposited cDNA (cDNA Clone ID). The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include, but are not limited to, preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.

Also provided in the present invention are allelic variants, orthologs, and/or species homologs. Procedures known in the art can be used to obtain full-length genes, allelic variants, splice variants, full-length coding portions, orthologs, and/or species homologs of genes corresponding to SEQ ID NO:X and SEQ ID NO:Y using information from the sequences disclosed herein or the clones deposited with the ATCC. For example, allelic variants and/or species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for allelic variants and/or the desired homologue.

The present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ID NO:X and/or a cDNA contained in ATCC Deposit No. Z. The present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X, and/or a polypeptide encoded by a cDNA contained in ATCC deposit No. Z. Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by the cDNA contained in ATCC Deposit No. Z, are also encompassed by the invention. The present invention further encompasses a polynucleotide comprising, or alternatively consisting of the complement of the nucleic acid sequence of SEQ ID NO:X, and/or the complement of the coding strand of the cDNA contained in ATCC Deposit No. Z. TABLE 1A NT 5′ 3′ 5′ AA Last ATCC SEQ NT NT NT 5′ NT of SEQ First AA First Deposit ID Total of of of First AA ID AA of of AA of Last Gene cDNA No: Z and NO: NT Clone Clone Start of Signal NO: Sig Sig Secreted AA of No. Clone ID Date Vector X Seq. Seq. Seq. Codon Pep Y Pep Pep Portion ORF 1 H6EDM64 203959 Uni-ZAP 11 2610 1275 2377 1448 1448 274 1 6 Apr. 26, 1999 XR 2 H6EEU40 203917 Uni-ZAP 12 951 1 951 175 175 275 1 27 28 47 Apr. 08, 1999 XR 3 HACBJ56 203979 Uni-ZAP 13 888 1 888 250 276 1 9 10 25 Apr. 29, 1999 XR 4 HACBS22 203979 Uni-ZAP 14 3239 1 3239 217 217 277 1 23 24 41 Apr. 29, 1999 XR 5 HACBT91 203917 Uni-ZAP 15 841 1 841 329 278 1 7 8 59 Apr. 08, 1999 XR 6 HADDJ13 203917 pSport1 16 2318 1 2318 347 347 279 1 20 21 30 Apr. 08, 1999 7 HADMA77 203917 pBluescript 17 1913 763 1913 992 280 1 14 15 23 Apr. 08, 1999 8 HADMB15 203979 pBluescript 18 330 1 330 238 281 1 11 12 20 Apr. 29, 1999 9 HAGBQ12 203917 Uni-ZAP 19 743 1 743 171 171 282 1 19 20 21 Apr. 08, 1999 XR 10 HAGCC87 203917 Uni-ZAP 20 1592 479 1592 509 509 283 1 9 Apr. 08, 1999 XR 11 HAGFJ67 PTA-181 Uni-ZAP 21 2122 1 2122 208 208 284 1 26 27 92 Jun. 07, 1999 XR 12 HAGFS57 203979 Uni-ZAP 22 874 1 874 241 241 285 1 26 27 54 Apr. 29, 1999 XR 13 HAGHN57 203917 Uni-ZAP 23 2440 843 2440 900 900 286 1 10 Apr. 08, 1999 XR 14 HAGHR18 203917 Uni-ZAP 24 1142 1 1142 28 28 287 1 17 18 32 Apr. 08, 1999 XR 15 HAJAA47 203917 pCMVSport 25 1237 1 1237 192 288 1 15 16 38 Apr. 08, 1999 3.0 16 HAJAY92 203959 pCMVSport 26 2345 1 2345 12 12 289 1 20 21 94 Apr. 26, 1999 3.0 17 HAJBV67 PTA-181 pCMVSport 27 2536 1 2536 605 605 290 1 19 20 359 Jun. 07, 1999 3.0 18 HAQBG57 203917 Uni-ZAP 28 1048 1 1031 170 291 1 15 16 56 Apr. 08, 1999 XR 19 HARAE26 203917 pBluescript 29 1245 1 1245 225 225 292 1 30 31 97 Apr. 08, 1999 SK− 20 HATCD80 203917 Uni-ZAP 30 1809 95 1809 296 296 293 1 23 24 37 Apr. 08, 1999 XR 21 HBAGD86 203917 pSport1 31 1713 293 1596 521 521 294 1 18 19 19 Apr. 08, 1999 22 HBGBC29 203917 Uni-ZAP 32 1856 764 1829 1016 295 1 2 Apr. 08, 1999 XR 23 HBHAA05 203917 Uni-ZAP 33 690 1 690 110 296 1 16 17 58 Apr. 08, 1999 XR 24 HBHAA81 203959 Uni-ZAP 34 1647 1 1647 28 28 297 1 24 25 203 Apr. 26, 1999 XR 25 HBJAB02 203917 Uni-ZAP 35 1693 1 1665 84 84 298 1 27 28 34 Apr. 08, 1999 XR 26 HBJAC40 203979 Uni-ZAP 36 1767 184 1729 329 299 1 13 Apr. 29, 1999 XR 27 HBJCR46 203917 Uni-ZAP 37 3208 2270 3202 589 589 300 1 1 2 733 Apr. 08, 1999 XR 28 HBJDW56 203917 Uni-ZAP 38 637 1 637 121 301 1 8 Apr. 08, 1999 XR 29 HBJEL16 203979 Uni-ZAP 39 750 1 750 115 115 302 1 24 25 36 Apr. 29, 1999 XR 30 HBJFK45 203917 Uni-ZAP 40 543 1 543 430 303 1 8 Apr. 08, 1999 XR 31 HBJKD16 203979 Uni-ZAP 41 1629 1 1629 78 78 304 1 18 19 31 Apr. 29, 1999 XR 32 HBMUH74 PTA-181 Uni-ZAP 42 726 1 726 344 344 305 1 13 14 28 Jun. 07, 1999 XR 33 HBQAB79 203917 Lambda 43 1331 1 1331 190 190 306 1 11 Apr. 08, 1999 ZAP II 34 HBXCM66 203917 ZAP 44 1010 41 1010 119 119 307 1 16 Apr. 08, 1999 Express 35 HBXCX15 203917 ZAP 45 1219 1 1219 1148 308 1 1 Apr. 08, 1999 Express 36 HCDBO32 203917 Uni-ZAP 46 2630 1480 2630 1669 1669 309 1 25 26 71 Apr. 08, 1999 XR 37 HCEDR26 203917 Uni-ZAP 47 1419 1 1419 177 177 310 1 26 27 55 Apr. 08, 1999 XR 38 HCEEE79 203917 Uni-ZAP 48 1052 1 1052 131 131 311 1 15 16 55 Apr. 08, 1999 XR 39 HGEFG93 203917 Uni-ZAP 49 2280 1 2280 166 312 1 13 Apr. 08, 1999 XR 40 HCEFZ82 203917 Uni-ZAP 50 1811 44 1781 215 215 313 1 16 17 265 Apr. 08, 1999 XR 41 HCFLN88 203917 pSport1 51 1434 1 1434 101 101 314 1 16 17 25 Apr. 08, 1999 42 HCHAB84 203979 pSport1 52 1359 62 1359 304 315 1 23 24 147 Apr. 29, 1999 43 HCLBK61 203979 Lambda 53 1588 574 1563 1050 316 1 18 19 29 Apr. 29, 1999 ZAP II 44 HCMSX51 203917 Uni-ZAP 54 2253 334 2190 539 317 1 31 32 80 Apr. 08, 1999 XR 45 HCNCO11 203917 Lambda 55 746 1 746 101 101 318 1 14 Apr. 08, 1999 ZAP II 46 HCNSD29 PTA-181 pBluescript 56 1728 1031 1633 1145 1145 319 1 19 20 31 Jun. 07, 1999 47 HCQBH72 203917 Lambda 57 1796 776 1796 31 31 320 1 25 26 47 Apr. 08, 1999 ZAP II 48 HCQCC96 203979 Lambda 58 2166 632 1455 782 782 321 1 20 21 45 Apr. 29, 1999 ZAP II 49 HCUDD64 203917 ZAP 59 402 150 389 256 256 322 1 35 36 49 Apr. 08, 1999 Express 50 HCWAE64 203917 ZAP 60 471 1 471 410 323 1 5 Apr. 08, 1999 Express 51 HDPCW16 203960 pCMVSport 61 1536 1 1536 172 172 324 1 38 39 55 Apr. 26, 1999 3.0 52 HDPDI72 PTA-794 pCMVSport 62 1550 1 1550 23 23 325 1 17 18 120 Sep. 27, 1999 3.0 53 HDPGE24 203960 pCMVSport 63 2625 1 2625 173 173 326 1 11 12 73 Apr. 26, 1999 3.0 54 HDPIE44 PTA-794 pCMVSport 64 4115 1 4115 169 169 327 1 35 36 60 Sep. 27, 1999 3.0 55 HDPIU94 203960 pCMVSport 65 2196 21 2196 208 208 328 1 21 22 23 Apr. 26, 1999 3.0 56 HDPIY31 PTA-793 pCMVSport 66 1978 1 1978 268 268 329 1 16 17 35 Sep. 27, 1999 3.0 57 HDPOC24 203960 pCMVSport 67 1777 302 1725 418 418 330 1 23 24 133 Apr. 26, 1999 3.0 58 HDPPD93 203960 pCMVSport 68 701 1 701 28 28 331 1 12 Apr. 26, 1999 3.0 59 HDPPQ30 203960 pCMVSport 69 1063 1 1063 220 220 332 1 22 23 38 Apr. 26, 1999 3.0 60 HDQHM36 PTA-181 pCMVSport 70 1547 1 1547 129 129 333 1 18 19 48 Jun. 07, 1999 3.0 61 HDTLM18 203960 pCMVSport 71 525 1 525 345 345 334 1 18 19 60 Apr. 26, 1999 2.0 62 HE2CM39 203960 Uni-ZAP 72 566 1 566 10 335 1 13 Apr. 26, 1999 XR 63 HE6CS65 203960 Uni-ZAP 73 1526 1 1526 295 336 1 10 11 62 Apr. 26, 1999 XR 64 HE6FU11 203979 Uni-ZAP 74 2000 1 1994 145 145 337 1 26 27 226 Apr. 29, 1999 XR 65 HE6FV29 203960 Uni-ZAP 75 1526 1 1526 210 210 338 1 18 19 33 Apr. 26, 1999 XR 66 HE8BQ49 203960 Uni-ZAP 76 1875 12 1875 133 133 339 1 11 Apr. 26, 1999 XR 67 HE8SG96 PTA-181 Uni-ZAP 77 2036 1 2036 118 118 340 1 17 18 24 Jun. 07, 1999 XR 68 HE9EA10 203960 Uni-ZAP 78 2114 1 2111 212 341 1 28 29 78 Apr. 26, 1999 XR 69 HE9GG20 203960 Uni-ZAP 79 676 1 676 319 319 342 1 9 Apr. 26, 1999 XR 70 HEAAW94 203979 Uni-ZAP 80 924 1 924 189 189 343 1 11 Apr. 29, 1999 XR 71 HEBCI18 203960 Uni-ZAP 81 1121 713 1050 855 855 344 1 43 44 69 Apr. 26, 1999 XR 72 HEBCY54 203960 Uni-ZAP 82 1189 1 1189 172 172 345 1 24 25 118 Apr. 26, 1999 XR 73 HEBDQ91 203960 Uni-ZAP 83 1573 1007 1573 1211 346 1 29 30 41 Apr. 26, 1999 XR 74 HEBFR46 203979 Uni-ZAP 84 1304 1 1304 200 200 347 1 26 27 29 Apr. 29, 1999 XR 75 HEBGE07 203960 Uni-ZAP 85 1867 1 1867 106 106 348 1 25 26 42 Apr. 26, 1999 XR 76 HEBGE23 203960 Uni-ZAP 86 419 1 419 153 153 349 1 31 32 81 Apr. 26, 1999 XR 77 HEGAU15 203960 Uni-ZAP 87 1125 1 1125 59 59 350 1 30 31 34 Apr. 26, 1999 XR 78 HFCEI04 203960 Uni-ZAP 88 887 1 887 136 351 1 17 18 42 Apr. 26, 1999 XR 79 HFEAY59 203960 Uni-ZAP 89 1153 1 1153 154 154 352 1 24 25 40 Apr. 26, 1999 XR 80 HFEBO17 PTA-181 Uni-ZAP 90 990 1 990 136 136 353 1 17 18 27 Jun. 7, 1999 XR 81 HFIJA68 203979 pSport1 91 1157 1 1157 283 283 354 1 22 23 43 Apr. 29, 1999 82 HFKES05 203960 Uni-ZAP 92 1885 1 1885 243 243 355 1 17 18 42 Apr. 26, 1999 XR 83 HFKFX64 203960 Uni-ZAP 93 779 1 779 127 127 356 1 14 Apr. 26, 1999 XR 84 HFPCZ55 203960 Uni-ZAP 94 2735 341 2735 676 676 357 1 24 25 44 Apr. 26, 1999 XR 85 HFTAS49 203979 Uni-ZAP 95 518 1 518 249 249 358 1 19 20 23 Apr. 29, 1999 XR 86 HFVHW43 203960 pBluescript 96 1233 1 1233 92 92 359 1 30 31 39 Apr. 26, 1999 87 HGBER72 203960 Uni-ZAP 97 1316 1 1316 43 43 360 1 16 17 19 Apr. 26, 1999 XR 88 HGBHP91 203960 Uni-ZAP 98 1054 1 1054 50 361 1 14 15 52 Apr. 26, 1999 XR 89 HGLBG15 203960 Uni-ZAP 99 778 1 778 191 362 1 26 Apr. 26, 1999 XR 90 HHEAK45 203960 pCMVSport 100 2014 87 1935 813 363 1 3 Apr. 26, 1999 3.0 91 HHEOW19 PTA-793 pCMVSport 101 1589 1 1589 183 183 364 1 18 19 64 Sep. 27, 1999 3.0 92 HHFEB79 PTA-181 Uni-ZAP 102 3168 1 3168 120 120 365 1 18 19 756 Jun. 7, 1999 XR 92 HHFEB79 PTA-181 Uni-ZAP 256 2443 1 2443 715 715 519 1 18 19 571 Jun. 7, 1999 XR 93 HHFEC39 203960 Uni-ZAP 103 1302 1 1302 1211 366 1 1 Apr. 26, 1999 XR 94 HHFFS40 203960 Uni-ZAP 104 1816 1 1816 37 37 367 1 18 19 47 Apr. 26, 1999 XR 95 HHGCS78 203960 Lambda 105 575 46 575 290 290 368 1 17 18 24 Apr. 26, 1999 ZAP II 96 HHPFP26 203960 Uni-ZAP 106 2352 1 2352 24 369 1 27 28 80 Apr. 26, 1999 XR 97 HHPFU28 203960 Uni-ZAP 107 1838 1 1838 156 370 1 18 19 27 Apr. 26, 1999 XR 98 HHSBI06 203959 Uni-ZAP 108 1049 27 803 690 371 1 5 Apr. 26, 1999 XR 99 HHSBI65 203917 Uni-ZAP 109 1444 1 1431 62 62 372 1 17 18 55 Apr. 8, 1999 XR 100 HISAT67 203959 pSport1 110 2154 1061 2142 1239 1239 373 1 35 36 56 Apr. 26, 1999 101 HISBA38 203957 pSport1 111 1058 1 1058 169 169 374 1 32 33 36 Apr. 26, 1999 102 HJBCU75 203957 pBluescript 112 1009 1 1009 61 61 375 1 5 Apr. 26, 1999 SK− 103 HJMAA03 203957 pCMVSport 113 665 1 665 527 376 1 9 Apr. 26, 1999 3.0 104 HJPCH08 203959 Uni-ZAP 114 879 1 879 374 377 1 10 11 117 Apr. 26, 1999 XR 105 HKABU43 203959 pCMVSport 115 1919 581 1919 755 755 378 1 20 21 281 Apr. 26, 1999 2.0 106 HKIXC44 203957 pBluescript 116 788 343 750 572 572 379 1 26 27 36 Apr. 26, 1999 107 HKTAB41 203957 Uni-ZAP 117 797 1 797 172 172 380 1 10 Apr. 26, 1999 XR 108 HLDBG17 PTA-181 pCMVSport 118 652 1 652 184 184 381 1 23 24 41 Jun. 7, 1999 3.0 109 HLDQU79 203959 pCMVSport 119 1488 1 1488 99 99 382 1 23 24 348 Apr. 26, 1999 3.0 109 HLDQU79 203959 pCMVSport 257 3179 163 1474 75 75 520 1 29 30 348 Apr. 26, 1999 3.0 110 HLHAP05 203957 Uni-ZAP 120 1842 12 1842 45 45 383 1 14 Apr. 26, 1999 XR 111 HLHBS54 203957 Uni-ZAP 121 4038 2309 4023 73 73 384 1 1 2 343 Apr. 26, 1999 XR 112 HLHCS23 203957 Uni-ZAP 122 1427 1 1427 25 25 385 1 24 25 34 Apr. 26, 1999 XR 113 HLICE88 203957 pCMVSport1 123 840 401 824 708 386 1 2 Apr. 26, 1999 114 HLQAS12 PTA-793 Lambda 124 2450 1 2450 305 305 387 1 11 12 12 Sep. 27, 1999 ZAP II 115 HLYAR30 203957 pSport1 125 854 1 854 562 562 388 1 1 2 97 Apr. 26, 1999 116 HLYDF73 203957 pSport1 126 626 1 626 363 389 1 11 12 23 Apr. 26, 1999 117 HLYDO73 203957 pSport1 127 858 1 858 233 233 390 1 12 Apr. 26, 1999 118 HLYGY91 203957 pSport1 128 640 1 640 211 211 391 1 20 21 42 Apr. 26, 1999 119 HMDAB29 203957 Uni-ZAP 129 1190 1 1190 97 97 392 1 17 18 26 Apr. 26, 1999 XR 120 HMDAD44 203957 Uni-ZAP 130 1204 1 1204 135 135 393 1 8 Apr. 26, 1999 XR 121 HMEDE24 203957 Lambda 131 2836 884 2806 900 900 394 1 16 17 33 Apr. 26, 1999 ZAP II 122 HMEDI90 203957 Lambda 132 2276 362 2219 622 395 1 12 13 17 Apr. 26, 1999 ZAP II 123 HMIBD93 203957 Uni-ZAP 133 1323 734 1323 983 396 1 27 28 65 Apr. 26, 1999 XR 124 HMIBF07 203957 Uni-ZAP 134 1738 1 1738 229 229 397 1 6 Apr. 26, 1999 XR 125 HMJAK70 203957 pSport1 135 799 1 799 273 273 398 1 10 Apr. 26, 1999 126 HMQAI38 203957 Uni-ZAP 136 1777 1 1777 24 24 399 1 20 Apr. 26, 1999 XR 127 HMSHY25 PTA-793 Uni-ZAP 137 2205 1 2205 656 400 1 11 12 35 Sep. 27, 1999 XR 128 HMUAN45 203918 pCMVSport 138 2709 1 2709 239 239 401 1 25 26 227 Apr. 8, 1999 3.0 129 HMVBC31 203957 pSport1 139 2556 1327 2546 1437 1437 402 1 32 33 40 Apr. 26, 1999 130 HMWBL03 203957 Uni-ZAP 140 2596 80 2596 137 137 403 1 1 2 397 Apr. 26, 1999 XR 131 HMWCG28 203979 Uni-ZAP 141 893 1 893 78 78 404 1 30 31 40 Apr. 29, 1999 XR 132 HNECW49 203957 Uni-ZAP 142 489 1 463 316 316 405 1 20 21 58 Apr. 26, 1999 XR 133 HNFCY57 PTA-791 Uni-ZAP 143 2847 1 2847 317 317 406 1 10 11 629 Sep. 27, 1999 XR 134 HNFGR08 203957 Uni-ZAP 144 1436 1 1436 314 407 1 17 18 43 Apr. 26, 1999 XR 135 HNGAK51 203957 Uni-ZAP 145 915 1 915 248 248 408 1 23 24 32 Apr. 26, 1999 XR 136 HNGDX18 PTA-181 Uni-ZAP 146 1425 1 1425 237 237 409 1 30 31 243 Jun. 7, 1999 XR 136 HNGDX18 PTA-181 Uni-ZAP 258 1411 1 1411 231 231 521 1 18 19 132 Jun. 7, 1999 XR 137 HNGFR54 203957 Uni-ZAP 147 495 1 495 73 410 1 36 37 52 Apr. 26, 1999 XR 138 HNGGA68 203957 Uni-ZAP 148 585 1 585 184 184 411 1 32 Apr. 26, 1999 XR 139 HNGHK37 203957 Uni-ZAP 149 1543 1 1543 234 234 412 1 12 Apr. 26, 1999 XR 140 HNGIV64 203957 Uni-ZAP 150 1047 1 1047 221 413 1 8 Apr. 26, 1999 XR 141 HNGJB41 PTA-181 Uni-ZAP 151 1246 1 1246 252 252 414 1 46 47 73 Jun. 07, 1999 XR 142 HNGKT41 203959 Uni-ZAP 152 1048 1 1048 415 415 415 1 17 18 45 Apr. 26, 1999 XR 143 HNGMW45 203959 Uni-ZAP 153 1530 1 1530 452 452 416 1 26 27 43 Apr. 26, 1999 XR 144 HNGNO53 203959 Uni-ZAP 154 825 1 825 467 467 417 1 15 16 34 Apr. 26, 1999 XR 145 HNGPJ25 203959 Uni-ZAP 155 853 129 853 544 544 418 1 20 21 25 Apr. 26, 1999 XR 146 HNHCT47 203959 Uni-ZAP 156 621 12 621 73 73 419 1 20 21 39 Apr. 26, 1999 XR 147 HNHKI74 203959 Uni-ZAP 157 817 1 817 127 127 420 1 10 Apr. 26, 1999 XR 148 HNHKV56 203959 Uni-ZAP 158 1653 1 1653 294 294 421 1 31 32 66 Apr. 26, 1999 XR 149 HOACG07 203959 Uni-ZAP 159 1298 772 1249 778 778 422 1 21 22 123 Apr. 26, 1999 XR 150 HODBB70 203918 Uni-ZAP 160 604 1 604 173 423 1 7 8 27 Apr. 08, 1999 XR 151 HOEBK60 203959 Uni-ZAP 161 2218 1449 2216 1714 1714 424 1 39 40 43 Apr. 26, 1999 XR 152 HOFMO16 203918 pCMVSport 162 1142 1 1142 149 149 425 1 40 41 152 Apr. 08, 1999 2.0 153 HOFNB74 203959 pCMVSport 163 1036 1 1036 138 138 426 1 24 25 39 Apr. 26, 1999 2.0 154 HOHBO66 PTA-181 pCMVSport 164 1790 1 1790 338 338 427 1 21 Jun. 07, 1999 2.0 155 HORBS82 203959 Uni-ZAP 165 1125 1 1125 21 428 1 19 20 39 Apr. 26, 1999 XR 156 HORBV76 203959 Uni-ZAP 166 1157 1 1157 183 183 429 1 25 26 198 Apr. 26, 1999 XR 157 HOSDO75 PTA-181 Uni-ZAP 167 902 1 902 88 88 430 1 28 Jun. 07, 1999 XR 158 HOSEI81 203918 Uni-ZAP 168 897 1 897 203 203 431 1 22 23 83 Apr. 08, 1999 XR 159 HOUDE92 203918 Uni-ZAP 169 1284 1 1282 70 432 1 6 7 88 Apr. 08, 1999 XR 160 HPCAL26 203917 Uni-ZAP 170 3097 803 3097 1021 1021 433 1 23 24 30 Apr. 08, 1999 XR 161 HPEAD23 203959 Uni-ZAP 171 582 1 582 188 188 434 1 13 14 93 Apr. 26, 1999 XR 162 HPEBA84 203959 Uni-ZAP 172 1160 250 1160 533 533 435 1 21 22 36 Apr. 26, 1999 XR 163 HPFCI36 PTA-181 Uni-ZAP 173 879 1 879 94 94 436 1 17 18 19 Jun. 07, 1999 XR 164 HPFDI37 PTA-181 Uni-ZAP 174 352 1 352 38 38 437 1 17 Jun. 07, 1999 XR 165 HPIAA80 203959 Uni-ZAP 175 919 312 919 314 438 1 13 14 37 Apr. 26, 1999 XR 166 HPJCW58 203918 Uni-ZAP 176 1165 1 1165 177 177 439 1 19 20 28 Apr. 08, 1999 XR 167 HPMCV30 203918 Uni-ZAP 177 908 1 908 52 52 440 1 27 28 47 Apr. 08, 1999 XR 168 HPRBH85 203959 Uni-ZAP 178 1673 558 1648 684 684 441 1 18 19 134 Apr. 26, 1999 XR 169 HPRCD35 PTA-181 Uni-ZAP 179 709 1 689 265 442 1 16 17 35 Jun. 07, 1999 XR 170 HPRCM72 203959 Uni-ZAP 180 2455 26 1572 281 443 1 24 25 108 Apr. 26, 1999 XR 171 HPTRE80 PTA-792 pBluescript 181 1173 1 1173 102 444 1 21 22 187 Sep. 27, 1999 172 HPTRI42 203959 pBluescript 182 1098 1 1098 266 445 1 18 19 71 Apr. 26, 1999 173 HPTRM02 203959 pBluescript 183 1760 658 1680 885 885 446 1 16 17 80 Apr. 26, 1999 174 HPTRQ52 203959 pBluescript 184 658 1 658 224 224 447 1 13 14 33 Apr. 26, 1999 175 HPTVI96 203959 pBluescript 185 520 1 520 271 271 448 1 6 Apr. 26, 1999 176 HPWBA29 203918 Uni-ZAP 186 325 1 325 194 194 449 1 13 Apr. 08, 1999 XR 177 HRDAI17 203918 Uni-ZAP 187 1500 547 1500 578 578 450 1 27 28 31 Apr. 08, 1999 XR 178 HRDDQ39 203959 Uni-ZAP 188 776 1 773 215 451 1 17 18 46 Apr. 26, 1999 XR 179 HRDEX93 203959 Uni-ZAP 189 1681 711 1638 649 649 452 1 20 21 72 Apr. 26, 1999 XR 180 HRTAP63 203979 pBluescript 190 2576 891 2576 959 959 453 1 28 29 42 Apr. 29, 1999 SK− 181 HSAVW42 203959 Uni-ZAP 191 595 1 595 129 129 454 1 16 17 22 Apr. 26, 1999 XR 182 HSAWN53 203959 Uni-ZAP 192 349 1 349 159 455 1 29 30 63 Apr. 26, 1999 XR 183 HSAWZ40 203959 Uni-ZAP 193 1019 1 1019 124 124 456 1 37 Apr. 26, 1999 XR 184 HSAYC41 203959 Uni-ZAP 194 214 1 214 106 106 457 1 16 17 36 Apr. 26, 1999 XR 185 HSDBI90 PTA-181 Uni-ZAP 195 1057 1 1057 218 218 458 1 14 Jun. 07, 1999 XR 186 HSHAX04 203959 Uni-ZAP 196 1287 494 1285 42 459 1 6 7 57 Apr. 26, 1999 XR 187 HSKDR27 203918 Uni-ZAP 197 762 1 762 473 460 1 11 12 27 Apr. 08, 1999 XR 188 HSNBM34 203959 Uni-ZAP 198 2186 1391 1765 1508 461 1 14 15 62 Apr. 26, 1999 XR 189 HSRFD18 203959 Uni-ZAP 199 1889 1 1793 67 67 462 1 20 21 28 Apr. 26, 1999 XR 190 HSSEF77 203959 Uni-ZAP 200 1053 1 1053 184 463 1 25 26 60 Apr. 26, 1999 XR 191 HSSGJ58 203918 Uni-ZAP 201 1954 1 1954 245 245 464 1 17 18 38 Apr. 08, 1999 XR 192 HSVBD37 203959 Uni-ZAP 202 464 1 464 146 146 465 1 6 Apr. 26, 1999 XR 193 HSYBI06 203918 pCMVSport 203 956 1 956 232 232 466 1 21 22 33 Apr. 08, 1999 3.0 194 HT4FV41 PTA-181 Uni-ZAP 204 1764 1 1764 39 467 1 16 17 137 Jun. 07, 1999 XR 195 HT5GR59 203959 Uni-ZAP 205 1743 1 1743 135 135 468 1 23 24 31 Apr. 26, 1999 XR 196 HTDAA78 203918 pSport1 206 825 1 825 151 151 469 1 20 Apr. 08, 1999 197 HTEAG62 203959 Uni-ZAP 207 2221 57 2221 1017 1017 470 1 20 21 22 Apr. 26, 1999 XR 198 HTECB02 203959 Uni-ZAP 208 1662 106 1662 196 196 471 1 22 23 56 Apr. 26, 1999 XR 199 HTEDJ28 203959 Uni-ZAP 209 1247 1 1247 287 472 1 18 19 45 Apr. 26, 1999 XR 200 HTEHU59 203959 Uni-ZAP 210 1523 1 1504 170 170 473 1 19 20 34 Apr. 26, 1999 XR 201 HTEJD29 203959 Uni-ZAP 211 1324 1 1324 101 101 474 1 23 Apr. 26, 1999 XR 202 HTEKM46 PTA-181 Uni-ZAP 212 2116 1 2116 171 171 475 1 24 25 38 Jun. 07, 1999 XR 203 HTENR63 PTA-792 Uni-ZAP 213 1591 1 1591 132 132 476 1 20 21 56 Sep. 27, 1999 XR 204 HTGBK95 203959 Uni-ZAP 214 1131 1 1131 271 271 477 1 12 13 16 Apr. 26, 1999 XR 205 HTGGM44 203959 Uni-ZAP 215 3016 1 2761 179 179 478 1 18 19 84 Apr. 26, 1999 XR 206 HTHBZ06 203959 Uni-ZAP 216 623 193 619 318 318 479 1 1 Apr. 26, 1999 XR 207 HTLBT80 203959 Uni-ZAP 217 2101 817 1881 912 912 480 1 27 28 129 Apr. 26, 1999 XR 208 HTLCX82 203979 Uni-ZAP 218 920 1 920 46 481 1 15 16 75 Apr. 29, 1999 XR 209 HTLDU78 203918 Uni-ZAP 219 1318 1 1318 219 219 482 1 8 Apr. 08, 1999 XR 210 HTLEV48 203918 Uni-ZAP 220 1070 1 1070 205 205 483 1 30 31 207 Apr. 08, 1999 XR 210 HTLEV48 203918 Uni-ZAP 259 1065 1 1065 91 91 522 1 9 Apr. 08, 1999 XR 211 HTLFA13 203918 Uni-ZAP 221 1160 1 1160 209 484 1 8 9 31 Apr. 08, 1999 XR 212 HTLGI89 203959 Uni-ZAP 222 2377 1205 2377 1802 1802 485 1 16 17 37 Apr. 26, 1999 XR 213 HTNBK13 203959 pBluescript 223 1160 295 1148 534 534 486 1 16 17 21 Apr. 26, 1999 SK− 214 HTOAM11 203918 Uni-ZAP 224 1200 1 1200 89 89 487 1 24 25 34 Apr. 08, 1999 XR 215 HTODH83 203918 Uni-ZAP 225 1981 1 1981 103 103 488 1 21 22 32 Apr. 08, 1999 XR 216 HTODN35 203918 Uni-ZAP 226 1594 1 1594 67 67 489 1 14 Apr. 08, 1999 XR 217 HTPCO75 PTA-181 Uni-ZAP 227 1467 1 1467 73 490 1 23 24 40 Jun. 07, 1999 XR 218 HTTCB60 PTA-181 Uni-ZAP 228 1504 1 1504 84 84 491 1 17 18 266 Jun. 07, 1999 XR 219 HTTDN24 203959 Uni-ZAP 229 1992 856 1992 1024 492 1 13 14 234 Apr. 26, 1999 XR 220 HTTEE41 203959 Uni-ZAP 230 1973 864 1968 1171 493 1 8 Apr. 26, 1999 XR 221 HTWEH94 203918 pSport1 231 1361 1 1361 66 66 494 1 43 44 81 Apr. 08, 1999 222 HTXDG92 203959 Uni-ZAP 232 1162 1 1162 216 495 1 24 25 66 Apr. 26, 1999 XR 223 HTXET11 203918 Uni-ZAP 233 989 1 989 178 178 496 1 22 23 29 Apr. 08, 1999 XR 224 HTXFA72 PTA-181 Uni-ZAP 234 1861 1 1861 192 192 497 1 17 18 29 Jun. 07, 1999 XR 225 HTXJD85 203959 Uni-ZAP 235 1117 1 1117 211 211 498 1 16 17 31 Apr. 26, 1999 XR 226 HTXJY08 203959 Uni-ZAP 236 1187 12 1187 108 108 499 1 16 Apr. 26, 1999 XR 227 HTXLT36 203959 Uni-ZAP 237 1040 1 1038 189 189 500 1 13 Apr. 26, 1999 XR 228 HUFCL31 203959 pSport1 238 1460 1 1460 287 501 1 26 Apr. 26, 1999 229 HUKDF20 203918 Lambda 239 1105 1 1105 214 214 502 1 20 21 33 Apr. 08, 1999 ZAP II 230 HUSCJ14 PTA-1838 Lambda 240 3342 1 3342 74 74 503 1 30 31 196 May 09, 2000 ZAP II 231 HUVDJ48 203918 Uni-ZAP 241 1827 1 1827 196 196 504 1 5 Apr. 08, 1999 XR 232 HWBBU75 203979 pCMVSport 242 2731 623 2731 783 783 505 1 22 23 51 Apr. 29, 1999 3.0 233 HWBCN36 203959 pCMVSport 243 1008 1 1008 378 378 506 1 23 24 90 Apr. 26, 1999 3.0 234 HWBDJ08 203959 pCMVSport 244 2085 1 2085 253 253 507 1 29 30 50 Apr. 26, 1999 3.0 235 HWLBO67 203959 pSport1 245 536 1 536 42 42 508 1 28 29 39 Apr. 26, 1999 236 HWLGP26 203959 pSport1 246 1898 1007 1835 1091 1091 509 1 23 24 71 Apr. 26, 1999 237 HILCA24 203960 pBluescript 247 1982 153 1982 191 191 510 1 29 30 327 Apr. 26, 1999 SK− 237 HILCA24 203960 pBluescript 260 1980 151 1976 189 189 523 1 29 30 327 Apr. 26, 1999 SK− 238 HYABC84 203959 pCMVSport 248 1478 833 1306 1080 1080 511 1 28 29 62 Apr. 26, 1999 3.0 238 HYABC84 203959 pCMVSport 261 1338 768 1238 1015 1015 524 1 28 29 62 Apr. 26, 1999 3.0 239 HPWTF23 203979 Uni-ZAP 249 2008 94 1994 283 283 512 1 29 30 130 Apr. 29, 1999 XR 239 HPWTF23 203979 Uni-ZAP 262 2008 94 1994 283 283 525 1 29 30 130 Apr. 29, 1999 XR 240 HLWAU42 203957 pCMVSport 250 947 1 947 220 220 513 1 17 18 57 Apr. 26, 1999 3.0 240 HLWAU42 203957 pCMVSport 263 2495 1542 2488 1751 1751 526 1 17 18 57 Apr. 26, 1999 3.0 241 HGCAC19 203960 pSport1 251 5061 23 1475 317 514 1 9 Apr. 26, 1999 241 HGCAC19 203960 pSport1 264 1771 21 1473 315 527 1 9 Apr. 26, 1999 241 HGCAC19 203960 pSport1 265 1534 23 1534 317 528 1 9 Apr. 26, 1999 242 HEQBJ01 203960 pCMVSport 252 2791 2346 2731 2603 2603 515 1 19 Apr. 26, 1999 3.0 242 HEQBJ01 203960 pCMVSport 266 2791 2346 2731 2603 2603 529 1 19 Apr. 26, 1999 3.0 242 HEQBJ01 203960 pCMVSport 267 669 1 662 505 505 530 1 19 Apr. 26, 1999 3.0 243 HBJHT01 203917 Uni-ZAP 253 1251 1 1251 200 200 516 1 20 21 21 Apr. 08, 1999 XR 243 HBJHT01 203917 Uni-ZAP 268 1252 1 1252 193 193 531 1 21 22 47 Apr. 08, 1999 XR 244 HE8FD92 203979 Uni-ZAP 254 3977 1986 3960 2141 2141 517 1 25 26 43 Apr. 29, 1999 XR 244 HE8FD92 203979 Uni-ZAP 269 1995 1 1978 157 157 532 1 25 26 43 Apr. 29, 1999 XR 244 HE8FD92 203979 Uni-ZAP 270 4102 2114 4085 2268 2268 533 1 25 26 43 Apr. 29, 1999 XR 244 HE8FD92 203979 Uni-ZAP 271 4907 2918 4890 2 534 1 1 2 471 Apr. 29, 1999 XR 244 HE8FD92 203979 Uni-ZAP 272 2908 918 2891 1074 1074 535 1 25 26 43 Apr. 29, 1999 XR 245 HBDAB91 203917 pSport1 255 1007 320 1007 671 671 518 1 19 20 29 Apr. 08, 1999 245 HBDAB91 203917 pSport1 273 687 1 687 351 351 536 1 19 20 29 Apr. 08, 1999

Table 1B (Comprised of Tables 1B.1 and 1B.2)

The first column in Table 1B.1 and Table 1B.2 provides the gene number in the application corresponding to the clone identifier. The second column in Table 1B.1 and Table 1B.2 provides a unique “Clone ID:” for the cDNA clone related to each contig sequence disclosed in Table 1B.1 and Table 1B.2. This clone ID references the cDNA clone which contains at least the 5′ most sequence of the assembled contig and at least a portion of SEQ ID NO:X as determined by directly sequencing the referenced clone. The referenced clone may have more sequence than described in the sequence listing or the clone may have less. In the vast majority of cases, however, the clone is believed to encode a full-length polypeptide. In the case where a clone is not full-length, a full-length cDNA can be obtained by methods described elsewhere herein. The third column in Table 1B.1 and Table 1B.2 provides a unique “Contig ID” identification for each contig sequence. The fourth column in Table 1B.1 and Table 1B.2 provides the “SEQ ID NO:” identifier for each of the contig polynucleotide sequences disclosed in Table 1B.

Table 1B.1

The fifth column in Table 1B.1, “ORF (From-To)”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence “SEQ ID NO:X” that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1B.1, column 6, as SEQ ID NO:Y. Where the nucleotide position number “To” is lower than the nucleotide position number “From”, the preferred ORF is the reverse complement of the referenced polynucleotide sequence. The sixth column in Table 1B.1 provides the corresponding SEQ ID NO:Y for the polypeptide sequence encoded by the preferred ORF delineated in column 5. In one embodiment, the invention provides an amino acid sequence comprising, or alternatively consisting of, a polypeptide encoded by the portion of SEQ ID NO:X delineated by “ORF (From-To)”. Also provided are polynucleotides encoding such amino acid sequences and the complementary strand thereto. Column 7 in Table 1B.1 lists residues comprising epitopes contained in the polypeptides encoded by the preferred ORF (SEQ ID NO:Y), as predicted using the algorithm of Jameson and Wolf, (1988) Comp. Appl. Biosci. 4:181-186. The Jameson-Wolf antigenic analysis was performed using the computer program PROTEAN (Version 3.11 for the Power MacIntosh, DNASTAR, Inc., 1228 South Park Street Madison, Wis.). In specific embodiments, polypeptides of the invention comprise, or alternatively consist of, at least one, two, three, four, five or more of the predicted epitopes as described in Table 1B. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.

Column 8 in Table 1B.1 provides a chromosomal map location for certain polynucleotides of the invention. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Each sequence in the UniGene database is assigned to a “cluster”; all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from a single gene. Chromosomal mapping data is often available for one or more sequence(s) in a UniGene cluster; this data (if consistent) is then applied to the cluster as a whole. Thus, it is possible to infer the chromosomal location of a new polynucleotide sequence by determining its identity with a mapped UniGene cluster.

A modified version of the computer program BLASTN (Altshul, et al., J. Mol. Biol. 215:403-410 (1990), and Gish, and States, Nat. Genet. 3:266-272) (1993) was used to search the UniGene database for EST or cDNA sequences that contain exact or near-exact matches to a polynucleotide sequence of the invention (the ‘Query’). A sequence from the UniGene database (the ‘Subject’) was said to be an exact match if it contained a segment of 50 nucleotides in length such that 48 of those nucleotides were in the same order as found in the Query sequence. If all of the matches that met this criteria were in the same UniGene cluster, and mapping data was available for this cluster, it is indicated in Table 1B under the heading “Cytologic Band”. Where a cluster had been further localized to a distinct cytologic band, that band is disclosed; where no banding information was available, but the gene had been localized to a single chromosome, the chromosome is disclosed.

Once a presumptive chromosomal location was determined for a polynucleotide of the invention, an associated disease locus was identified by comparison with a database of diseases which have been experimentally associated with genetic loci. The database used was the Morbid Map, derived from OMIM™ and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.) 2000. If the putative chromosomal location of a polynucleotide of the invention (Query sequence) was associated with a disease in the Morbid Map database, an OMIM reference identification number was noted in column 9, Table 1B.1, labelled “OMIM Disease Reference(s). Table 5 is a key to the OMIM reference identification numbers (column 1), and provides a description of the associated disease in Column 2.

Table 1B.2

Column 5, in Table 1B.2, provides an expression profile and library code:count for each of the contig sequences (SEQ ID NO:X) disclosed in Table 1B, which can routinely be combined with the information provided in Table 4 and used to determine the tissues, cells, and/or cell line libraries which predominantly express the polynucleotides of the invention. The first number in Table 1B.2, column 5 (preceding the colon), represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4. The second number in column 5 (following the colon) represents the number of times a sequence corresponding to the reference polynucleotide sequence was identified in the corresponding tissue/cell source. Those tissue/cell source identifier codes in which the first two letters are “AR” designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of ³³P dCTP, using oligo (dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after “[array code]:” represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissue(s) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression. TABLE 1B.1 AA SEQ SEQ ID ID Gene cDNA Contig NO: ORF NO: Cytologic No: Clone ID ID: X (From-To) Y Predicted Epitopes Band OMIM Disease Reference(s): 1 H6EDM64 841331 11 1448-1468 274 11q13 102200, 106100, 131100, 131100, 131100, 133780, 147050, 153700, 161015, 164009, 168461, 168461, 168461, 180721, 180840, 191181, 193235, 209901, 232600, 259700, 259770, 600045, 600319, 600528, 601884 2 H6EEU40 757048 12 175-318 275 11q12.1 106100, 147050, 259700, 259770, 600045, 601884 3 HACBJ56 847112 13 250-327 276 Arg-14 to Ile-24. 4 HACBS22 847113 14 217-342 277 Cys-2 to Leu-8. 5 HACBT91 789939 15 329-508 278 Ser-49 to Lys-59. 17q25.3 170500, 170500, 170500, 232300, 252900 6 HADDJ13 827273 16 347-439 279 7 HADMA77 783049 17  992-1063 280 8 HADMB15 847116 18 238-300 281 9 HAGBQ12 722205 19 171-236 282 10 HAGCC87 638587 20 509-538 283 11 HAGFJ67 861680 21 208-486 284 Cys-26 to Asp-31. 12 HAGFS57 847120 22 241-405 285 Met-1 to Lys-6. 15q15.3 114240, 224120, 600839, 602099 13 HAGHN57 773286 23 900-932 286 7q22-q32 126650, 126650, 154276, 173360, 173360, 180105, 190900, 222800, 246900, 602136, 602136, 602136, 602447 14 HAGHR18 655435 24  28-126 287 15 HAJAA47 534670 25 192-308 288 Leu-33 to Asp-38. 16 HAJAY92 845601 26  12-296 289 Lys-89 to Glu-94. 17 HAJBV67 866415 27  605-1684 290 Arg-24 to Trp-44, 10q23.33 157640, 174900, 236730, 600512 Leu-87 to Ser-93, Arg-119 to Trp-125, Pro-206 to Lys-211, Glu-280 to Trp-286. 18 HAQBG57 837545 28 170-340 291 Trp-10 to Lys-18, Val-32 to Cys-38, Asp-41 to Thr-47. 19 HARAE26 560598 29 225-518 292 Pro-52 to Cys-57. 20 HATCD80 826098 30 296-409 293 21 HBAGD86 838799 31 521-580 294 22 HBGBC29 691473 32 1016-1024 295 3q13.3 126451, 600882 23 HBHAA05 603174 33 110-286 296 24 HBHAA81 846465 34  28-639 297 3p21.32 116806, 168468, 182280, 600163 25 HBJAB02 837309 35  84-188 298 Arg-24 to Asp-31. 17q23 106180, 138700, 139250, 150200, 154275, 176960, 249000, 253250 26 HBJAC40 841235 36 329-370 299 16p13.3 141750, 141800, 141800, 141800, 141800, 141850, 141850, 141850, 141850, 141850, 156850, 186580, 191092, 600140, 600273, 601313, 601785 27 HBJCR46 815649 37  589-2787 300 Met-1 to Ala-8, Phe- 15q12 103581, 146150, 182279, 203200, 203200, 227220, 42 to Asp-57, Tyr- 601623, 601800, 601889, 602117 105 to Thr-110, His- 121 to Cys-127, Asp- 154 to Lys-181, Arg- 186 to Pro-210, Ala- 233 to Asp-252, Ser- 296 to Ser-306, Pro- 313 to Ser-320, Gln- 331 to Gly-346, Ser- 355 to Thr-360, Cys- 386 to Phe-395, Ser- 400 to Glu-425, Thr- 440 to Thr-446, Pro- 449 to Cys-466, Glu- 470 to Thr-509, Ser- 512 to Asp-533, Ala- 544 to Arg-550, Arg- 562 to Glu-571, Lys- 587 to Thr-594, Asp- 713 to Glu-733. 28 HBJDW56 520401 38 121-147 301 29 HBJEL16 847030 39 115-225 302 1q23.1- 107300, 131210, 136132, 145001, 173610, 249270, q23.2 601652 30 HBJFK45 531919 40 430-456 303 31 HBJKD16 853358 41  78-173 304 2p14 203800 32 HBMUH74 866160 42 344-430 305 12p11.22 112410, 135700, 168470, 200990 33 HBQAB79 810542 43 190-225 306 4q31.1 189800, 600983 34 HBXCM66 639039 44 119-169 307 35 HBXCX15 637542 45 72-77 308 36 HCDBO32 831942 46 1669-1884 309 Val-2 to Thr-7. 37 HCEDR26 771144 47 177-344 310 38 HCEEE79 560609 48 131-298 311 Gly-35 to Pro-41. 39 HCEFG93 745400 49 166-207 312 40 HCEFZ82 831745 50  215-1012 313 Tyr-30 to Gln-35, 3p23-cen Asn-114 to Lys-119, Ser-161 to Ala-171, Arg-183 to Gly-189, Pro-205 to Ala-211, Lys-231 to Trp-237, Gly-246 to Lys-265. 41 HCFLN88 610000 51 101-178 314 7q11.23 116860, 129900, 233700, 600079 42 HCHAB84 834326 52 304-747 315 Asn-47 to Leu-52, Tyr-134 to Trp-143. 43 HCLBK61 845659 53 1050-1139 316 19p13.12 143890, 151440, 600276, 601843 44 HCMSX51 788643 54 539-781 317 Leu-57 to Glu-66. 8p21 152760, 180100, 185430, 602629 45 HCNCO11 775086 55 101-145 318 46 HCNSD29 862314 56 1145-1240 319 2q23.3 47 HCQBH72 637548 57  31-174 320 48 HCQCC96 845066 58 782-919 321 49 HCUDD64 835082 59 256-402 322 Met-1 to Ser-6, Gln- 19p13.3 108725, 120700, 133171, 136836, 145981, 147141, 32 to Asn-39. 164953, 188070, 600957, 601238, 601846, 602216, 602477 50 HCWAE64 535893 60 410-427 323 51 HDPCW16 840358 61 172-339 324 Met-1 to Ser-7. 11q12- 106100, 133780, 147050, 259700, 259770, 600045, q13.1 601650, 601884 52 HDPDI72 897277 62  23-385 325 Arg-63 to Phe-72, Ile-114 to Phe-120. 53 HDPGE24 801947 63 173-394 326 54 HDPIE44 899328 64 169-351 327 55 HDPIU94 813352 65 208-279 328 8p21.1 138300, 240400, 602629 56 HDPIY31 886159 66 268-375 329 20q13.33 57 HDPOC24 777493 67 418-819 330 Pro-36 to Cys-42, 9q34.12 Pro-44 to Cys-54, Arg-100 to Gly-105. 58 HDPPD93 637588 68 28-66 331 59 HDPPQ30 684292 69 220-336 332 60 HDQHM36 852328 70 129-275 333 61 HDTLM18 836057 71 345-524 334 Ile-47 to Ser-60. 62 HE2CM39 553651 72 10-51 335 63 HE6CS65 762960 73 295-483 336 Trp-50 to Leu-55. 1q23.2 107300, 131210, 136132, 145001, 173610, 249270, 601652 64 HE6FU11 827236 74 145-825 337 65 HE6FV29 588454 75 210-311 338 66 HE8BQ49 589443 76 133-168 339 67 HE8SG96 862016 77 118-192 340 Tyr-16 to Gln-23. 68 HE9EA10 827796 78 212-448 341 Arg-6 to Trp-11. 69 HE9GG20 633719 79 319-348 342 70 HEAAW94 847340 80 189-224 343 3p14.3 150250, 164500, 277730, 600971, 601226 71 HEBCI18 831464 81  855-1064 344 Val-40 to Cys-45, 2q14.2 165320 Lys-58 to Thr-64. 72 HEBCY54 600355 82 172-528 345 Arg-18 to Lys-26, 8p22-p21 148370, 152760, 180100, 185430, 238600, 238600, Gly-35 to Ala-42, 238600, 238600, 600143, 601385, 602629 Gln-61 to Gly-67. 73 HEBDQ91 840288 83 1211-1336 346 74 HEBFR46 847064 84 200-289 347 Met-1 to Thr-6. 75 HEBGE07 798096 85 106-234 348 76 HEBGE23 836129 86 153-398 349 19q13.2 107741, 113900, 122720, 122720, 126340, 126391, 160900, 164731, 173850, 207750, 248600, 258501 77 HEGAU15 834379 87  59-163 350 78 HFCEI04 692438 88 136-264 351 Asn-21 to Gly-28. 79 HFEAY59 658685 89 154-276 352 Arg-2 to Lys-8, Arg- 22 to Lys-31. 80 HFEBO17 852218 90 136-219 353 81 HFIJA68 847074 91 283-414 354 82 HFKES05 827572 92 243-371 355 Ile-26 to Ala-42. 83 HFKFX64 566835 93 127-171 356 18q11 114400, 257220, 257220 84 HFPCZ55 840840 94 676-810 357 11p15 108985, 186921, 602092 85 HFTAS49 847386 95 249-320 358 6p21.2 150270, 248611, 601690 86 HFVHW43 570948 96  92-211 359 87 HGBER72 826710 97  43-102 360 88 HGBHP91 693011 98  50-208 361 89 HGLBG15 701990 99 191-271 362 90 HHEAK45 765278 100 813-824 363 6p21.33 248611 91 HHEOW19 886174 101 183-377 364 Ala-41 to Pro-57. 1q42 106150, 106150, 145260, 173870, 173870, 600759, 600996, 601744, 601975 92 HHFEB79 1300768 102  120-2390 365 Ala-31 to Val-38, Pro-63 to Gly-68, Gly-74 to Cys-87, Pro-93 to Asp-104, Arg-109 to Ser-121, Gln-128 to Thr-133, Thr-148 to Ser-163, Pro-170 to Leu-179, Val-183 to Ser-195, Pro-202 to Asp-219, Thr-243 to Lys-287, Leu-290 to Thr-307, Pro-309 to Ala-323, Pro-325 to Glu-331, Ser-333 to Lys-341, Lys-347 to Lys-354, Pro-364 to Ser-376, Ser-386 to Thr-399, Leu-402 to Pro-407, Pro-415 to Asp-438, Lys-444 to Ser-451, Lys-467 to Ser-479, Ser-500 to Thr-518, Pro-524 to Asn-529, Gly-538 to Gly-545, Ser-552 to Phe-558, Val-569 to Asp-575, Val-583 to Asp-590, Arg-618 to Trp-628, Glu-630 to Pro-635, Pro-642 to Ala-652, Ser-654 to Thr-660, Glu-708 to Pro-713, Ala-715 to Trp-732, Thr-738 to His-751. HHFEB79 863749 256  715-2430 519 Ala-31 to Val-38, Pro-63 to Gly-68, Gly-74 to Cys-87, Pro-93 to Asp-104, Arg-109 to Ser-121, Gln-128 to Thr-133, Thr-148 to Ser-163, Pro-170 to Leu-179, Val-183 to Glu-188. 93 HHFEC39 609873 103 1211-1216 366 6p22-p21 180297, 248611, 251000, 263200, 600211, 600701, 601690 94 HHFFS40 824059 104  37-180 367 5p14.1 123000 95 HHGCS78 634605 105 290-364 368 17q11.1 182138, 600881, 601954 96 HHPFP26 753269 106  24-266 369 Trp-46 to Pro-52, 14q23.1 107970, 182600, 182870, 182870, 182870 Val-67 to Gly-72. 97 HHPFU28 824573 107 156-239 370 Ser-12 to Tyr-17. 4q12 103600, 103600, 103600, 104150, 104150, 104500, 164920, 164920, 164920, 170650, 600900 98 HHSBI06 639097 108 690-707 371 99 HHSBI65 801910 109  62-229 372 Ala-16 to Val-35. 8q24.3 188450, 188450, 188450 100 HISAT67 843549 110 1239-1409 373 2p23.3 176830, 176830, 182601, 229800, 602134 101 HISBA38 561711 111 169-279 374 102 HJBCU75 638329 112 61-78 375 103 HJMAA03 824062 113 527-556 376 104 HJPCH08 840365 114 374-727 377 Glu-3 to Phe-9, Gln- 17 to Leu-50. 105 HKABU43 838573 115  755-1600 378 Ile-69 to Ala-74, Ala-122 to Ser-129, Thr-160 to Glu-170, Lys-197 to Arg-202. 106 HKIXC44 716213 116 572-682 379 107 HKTAB41 695732 117 172-204 380 108 HLDBG17 855953 118 184-309 381 Leu-29 to His-34. 109 HLDQU79 740755 119  99-1142 382 Leu-68 to Lys-74, Tyr-109 to Lys-115, Gln-200 to Val-205, Lys-207 to Lys-214, Glu-237 to Ile-244, Ala-271 to Thr-279, Ser-317 to Ser-329, Gln-342 to Gly-348. HLDQU79 837599 257  75-1121 520 110 HLHAP05 638476 120 45-89 383 Gln-4 to Leu-14. 111 HLHBS54 837503 121  73-1101 384 Glu-25 to Glu-36, Thr-51 to Asp-57, Leu-117 to Gly-129. 112 HLHCS23 560663 122  25-129 385 113 HLICE88 840321 123 708-716 386 4q28 107250, 134820, 134820, 134820, 134830, 134850, 134850, 181600, 189800, 266300 114 HLQAS12 886180 124 305-343 387 12p13.2- 103950, 200990, 601458, 602096 p12.3 115 HLYAR30 781249 125 562-852 388 Ala-2 to Arg-10, Arg-77 to Arg-97. 116 HLYDF73 566869 126 363-434 389 117 HLYDO73 584787 127 233-271 390 118 HLYGY91 658703 128 211-339 391 119 HMDAB29 584789 129  97-177 392 120 HMDAD44 566854 130 135-161 393 121 HMEDE24 837027 131  900-1001 394 Asn-17 to Asn-22, 6p25.1 Arg-27 to Lys-33. 122 HMEDI90 840077 132 622-675 395 Ser-7 to Thr-13. 123 HMIBD93 634227 133  983-1180 396 Pro-4 to Gly-13, Ala- 42 to Ser-50. 124 HMIBF07 603528 134 229-249 397 125 HMJAK70 610099 135 273-305 398 126 HMQAI38 589964 136 24-86 399 127 HMSHY25 886183 137 656-763 400 His-1 to Gln-6, Glu- 28 to Pro-35. 128 HMUAN45 833072 138 239-922 401 Pro-33 to Gly 45, 11q13.5 133780, 266150, 276903, 276903, 276903 Cys-121 to Gly-131, Ala-155 to His-166, Gly-180 to Gln-185. 129 HMVBC31 825598 139 1437-1559 402 Ser-33 to Tyr-39. 1p36.21 120550, 120570, 120575, 153454, 256700 130 HMWBL03 822861 140  137-1327 403 Met-1 to Leu-11, Val-13 to Lys-19, Thr-30 to Asp-39, Thr-49 to Gly-68, Ala-78 to Gly-111, Pro-140 to Thr-163, Ser-169 to Ser-185, Glu-197 to Lys-204, Lys-210 to Asp-215, Glu-220 to Ser-231, Ser-255 to Leu-266, Thr-269 to Asp-288, Cys-300 to Val-309, Phe-331 to Cys-339, Ser-362 to Ile-373. 131 HMWCG28 847413 141  78-200 404 12p13.3 103950, 193100, 193400, 200990, 601458 132 HNECW49 639117 142 316-489 405 Cys-21 toTrp-26, Val-37 to Ser-53. 133 HNFCY57 877653 143  317-2206 406 Leu-15 to Leu-25, 1q44 601975 Arg-47 to His-53, Glu-130 to Asn-138, Pro-140 to Ser-148, Asn-157 to Lys-163, Asn-178 to Lys-187, Pro-281 to Arg-292, Leu-341 to Leu-346, Lys-471 to Cys-477, Arg-513 to Gly-521, Gly-570 to Gly-575, Leu-614 to Glu-620. 134 HNFGR08 825417 144 314-445 407 135 HNGAK51 603910 145 248-346 408 136 HNGDX18 1145071 146 237-965 409 Ser-21 to Ser-39, Gln-45 to Gln-61, Cys-124 to Ser-139. HNGDX18 866177 258 231-629 521 Ser-21 to Ser-39, Gln-45 to Gln-61, Cys-124 to Gly-130. 137 HNGFR54 695748 147  73-231 410 Trp-6 to Tyr-11. 138 HNGGA68 638116 148 184-282 411 Ala-8 to Gly-20. 139 HNGHK37 609889 149 234-272 412 140 HNGIV64 561572 150 221-247 413 141 HNGJB41 852178 151 252-473 414 22q12.2 101000, 101000, 101000, 101000, 123620, 138981, 188826, 600850, 601669 142 HNGKT41 836061 152 415-552 415 143 HNGMW45 838613 153 452-583 416 144 HNGNO53 836063 154 467-571 417 145 HNGPJ25 834942 155 544-621 418 146 HNHCT47 634691 156  73-192 419 Asn-25 to Thr-33. 147 HNHKI74 777856 157 127-159 420 148 HNHKV56 800877 158 294-494 421 149 HOACG07 792928 159  778-1149 422 Pro-32 to Ser-42, 20p13 192340, 234200 Cys-51 to Gly-83, Gly-87 to Ser-93. 150 HODBB70 520196 160 173-256 423 151 HOEBK60 789396 161 1714-1845 424 Lys-5 to Thr-10, Gln-36 to Gly-43. 152 HOFMO16 596835 162 149-607 425 Arg-138 to Arg-143. 16p12- 108730, 147781, 172471, 182381, 186580, 266600, p11.2 600760, 600760, 600761, 600761, 602066 153 HOFNB74 762821 163 138-257 426 Ser-30 to Ser-36. 12q12- 181430, 600194, 600231, 600808, 601284, 601769, 12q14.3 601769, 602116 154 HOHBO66 853375 164 338-403 427 155 HORBS82 638293 165  21-140 428 Gly-30 to Ser-35. 156 HORBV76 839270 166 183-779 429 Gly-25 to Leu-38, Asp-56 to Gly-65, Ser-115 to Lys-121. 157 HOSDO75 862049 167  88-174 430 Phe-2 to Ser-8, Phe- 11q13.4 133780, 266150 21 to Ser-26. 158 HOSEI81 562778 168 203-454 431 Lys-70 to Asn-76. 12q12- 107777, 123940, 139350, 139350, 148040, 148041, q13 148043, 148070, 231550, 600194, 600231, 600536, 600808, 600956, 601284, 601769, 601769, 601928, 602116, 602153 159 HOUDE92 580866 169  70-336 432 Pro-22 to His-31, Ser-80 to Gln-88. 160 HPCAL26 762822 170 1021-1113 433 12 161 HPEAD23 773409 171 188-469 434 Ala-54 to Lys-59. 162 HPEBA84 753957 172 533-643 435 163 HPFCI36 855966 173  94-153 436 10q23.31 157640, 174900, 236730, 600512 164 HPFDI37 862056 174 38-91 437 22q11.21 123620, 151410, 600850 165 HPIAA80 829972 175 314-427 438 166 HPJCW58 612866 176 177-263 439 Leu-16 to Gly-21. 167 HPMCV30 612870 177  52-195 440 Leu-39 to His-47. 168 HPRBH85 695752 178  684-1088 441 Glu-121 to Leu-126. 3q21.1 106165, 117700, 117700, 150210, 169600, 180380, 180380, 180380, 203500, 232050, 276902, 600882, 601199, 601199, 601199, 601471, 601682 169 HPRCD35 853551 179 265-372 442 Asp-16 to Gln-27. 170 HPRCM72 813512 180 281-607 443 Arg-76 to Lys-91. 171 HPTRE80 884167 181 102-665 444 Gly-35 to Ser-40, 22q13.33 Ser-61 to Arg-72, Pro-148 to Arg-172. 172 HPTRI42 655362 182 266-481 445 Pro-19 to Pro-26, 11q13.1 106100, 133780, 601650 Gly-33 to Ser-38, Gly-45 to Tyr-52, Ser-65 to Ser-71. 173 HPTRM02 812879 183  885-1127 446 His-48 to Ser-61, 7 Ala-66 to Val-72. 174 HPTRQ52 655363 184 224-325 447 1p34 130500, 133200, 138140, 168360, 171760, 171760, 176100, 176100, 178300, 230000, 255800 175 HPTVI96 636064 185 271-291 448 16p13.3 141750, 141800, 141800, 141800, 141800, 141850, 141850, 141850, 141850, 141850, 156850, 186580, 191092, 600140, 600273, 601313, 601785 176 HPWBA29 561956 186 194-235 449 177 HRDAI17 560720 187 578-673 450 178 HRDDQ39 840405 188 215-355 451 Gly-27 to Pro-35. 179 HRDEX93 816046 189 649-867 452 1p34 130500, 133200, 138140, 168360, 171760, 171760, 176100, 176100, 178300, 230000, 255800 180 HRTAP63 780698 190  959-1087 453 Asn-2 to Trp-13. 2p23.3 176830, 176830, 182601, 229800, 602134 181 HSAVW42 637660 191 129-197 454 3p22.3 182280, 227646, 261510, 600163, 601154 182 HSAWN53 634697 192 159-347 455 Gln-42 to Ser-63. 183 HSAWZ40 634000 193 124-237 456 184 HSAYC41 688057 194 106-213 457 Lys-23 to Lys-36. 11q12.1 106100, 147050, 259700, 259770, 600045, 601884 185 HSDBI90 853376 195 218-262 458 186 HSHAX04 812178 196  42-215 459 1p32 120950, 120960, 138140, 178300, 187040, 600101, 600650, 600650, 600722, 600722 187 HSKDR27 580874 197 473-556 460 Pro-18 to Gly-26. 19p13.2 108725, 120700, 133171, 143890, 147670, 147670, 147670, 151440, 164953, 231670, 600276, 600957, 601843 188 HSNBM34 635131 198 1508-1696 461 Ala-17 to Thr-26, 17p13- 100710, 138190, 254210, 271900, 600179, 600977, Gly-49 to Gln-62. p11 601202, 601777 189 HSRFD18 840771 199  67-153 462 190 HSSEF77 658725 200 184-366 463 Arg-22 to Lys-27, 2p12 147200, 178640, 216900 Leu-30 to Asn-39. 191 HSSGJ58 747714 201 245-361 464 Thr-14 to Gln-34. 192 HSVBD37 637110 202 146-166 465 1p22-p21 102770, 120280, 120280, 166600, 170995, 191540, 232400, 232400, 274270, 274270, 600309, 601414, 601691, 601691, 601691, 601691, 601718, 602094 193 HSYBI06 740766 203 232-333 466 194 HT4FV41 853400 204  39-452 467 Ala-15 to Gln-22, 19p13.3 108725, 120700, 133171, 136836, 145981, 147141, Gly-36 to Gly-41, 164953, 188070, 600957, 601238, 601846, 602216, Arg-47 to Pro-63, 602477 Pro-85 to His-98. 195 HT5GR59 801930 205 135-230 468 8p21.3 602629 196 HTDAA78 566861 206 151-213 469 Ala-5 to Leu-18. 1q25.1 145001, 150292, 208250, 600995, 601652 197 HTEAG62 812332 207 1017-1085 470 198 HTECB02 806305 208 196-366 471 Ser-3 to Arg-9, Ser- 14q32 123270, 245200, 251600, 270100, 276900 19 to Pro-28, Arg-34 to Ala-43. 199 HTEDJ28 762845 209 287-424 472 Thr-34 to Leu-41. 8p22-q11 148370, 180100, 238600, 238600, 238600, 238600, 600143, 601385, 602629 200 HTEHU59 840385 210 170-274 473 Ser-29 to Phe-34. 201 HTEJD29 695798 211 101-172 474 202 HTEKM46 862069 212 171-287 475 203 HTENR63 877952 213 132-302 476 Pro-22 to Lys-28. 4q24 157147, 248510 204 HTGBK95 834490 214 271-321 477 205 HTGGM44 842856 215 179-433 478 3q23 106165, 110100, 117700, 117700, 150210, 169600, 180380, 180380, 180380, 203500, 276902, 601199, 601199, 601199, 601682 206 HTHBZ06 832477 216 318-323 479 12q24.31 181405 207 HTLBT80 840045 217  912-1301 480 Ser-107 to Ser-116. 20q11.21- 102700, 102700, 602025 q13.11 208 HTLCX82 847091 218  46-273 481 Glu-48 to Gly-60, 22q11.21 123620, 151410, 600850 Pro-68 to Trp-74. 209 HTLDU78 637702 219 219-245 482 210 HTLEV48 723799 220 205-825 483 Met-1 to Arg-12, 22q11.2- 123620, 138720, 145410, 188826, 231950, 239500, Thr-19 to Leu-27, q12.1 275350, 600850, 601669 Asp-72 to Val-79, Arg-89 to Pro-94, Lys-102 to Ser-111, Glu-116 to Arg-122, Lys-134 to Pro-142, Ser-146 to Ser-151, Gly-177 to Asp-196. HTLEV48 566786 259  91-120 522 211 HTLFA13 535937 221 209-304 484 212 HTLGI89 835069 222 1802-1915 485 213 HTNBK13 831967 223 534-599 486 22q12 123620, 133450, 133450, 600850, 601669 214 HTOAM11 664508 224  89-193 487 215 HTODH83 580884 225 103-201 488 216 HTODN35 570901 226  67-111 489 217 HTPCO75 853645 227  73-195 490 218 HTTCB60 853401 228  84-884 491 Ser-83 to Asp-88, Val-166 to Gly-181, Pro-193 to Ala-199, Glu-235 to Gln-250. 219 HTTDN24 766485 229 1024-1728 492 Asp-194 to Leu-199, 19q13.42 Ile-206 to Pro-211, Glu-224 to Ser-229. 220 HTTEE41 840950 230 1171-1197 493 12q15 181430, 600698, 600698, 600698, 600698, 600808, 602116 221 HTWEH94 561680 231  66-311 494 222 HTXDG92 658730 232 216-416 495 17q11.2 154275, 162200, 162200, 182138, 239100, 600881, 601954, 602403 223 HTXET11 581521 233 178-267 496 224 HTXFA72 853410 234 192-281 497 225 HTXJD85 840391 235 211-306 498 226 HTXJY08 637774 236 108-158 499 227 HTXLT36 843477 237 189-230 500 4p16 225500, 600593, 602363 228 HUFCL31 801938 238 287-367 501 9p21 108120, 112250, 247640, 600160, 600221, 601606 229 HUKDF20 566823 239 214-315 502 230 HUSCJ14 894699 240  74-661 503 Phe-166 to Arg-174, Ser-191 to Tyr-196. 231 HUVDJ48 564853 241 196-213 504 232 HWBBU75 780360 242 783-938 505 Ser-17 to Gly-22, Leu-34 to Ala-42. 233 HWBCN36 722259 243 378-650 506 Lys-45 to Pro-51, Arg-80 to Arg-85. 234 HWBDJ08 762860 244 253-405 507 Ser-30 to Gly-36. 235 HWLBO67 834315 245  42-161 508 236 HWLGP26 834770 246 1091-1306 509 Pro-26 to Met-35. 7p13 138079, 138079, 165240, 165240, 165240, 180104, 203740, 219800, 261670, 601649 237 HILCA24 869856 247  191-1174 510 Gln-52 to Arg-57, 5p15.2 123000, 602568 Glu-74 to Leu-84, Val-104 to Asp-110, Gly-157 to Gly-163, Asn-185 to Ser-195, Arg-245 to Asp-250, Pro-302 to Pro-310, Thr-316 to Tyr-322. HILCA24 782450 260  189-1172 523 Gln-52 to Arg-57, Glu-74 to Leu-84, Val-104 to Asp-110, Gly-157 to Gly-163, Asn-185 to Ser-195, Arg-245 to Asp-250, Pro-302 to Pro-310, Thr-316 to Tyr-322. 238 HYABC84 865064 248 1080-1268 511 Pro-3 to Ala-8. 20q11.22 HYABC84 789854 261 1015-1203 524 Pro-3 to Ala-8. 239 HPWTF23 844775 249 283-675 512 Val-80 to Leu-92, Ser-98 to Lys-104, Pro-111 to Pro-122. HPWTF23 843700 262 283-675 525 Val-80 to Leu-92, Ser-98 to Lys-104, Pro-111 to Pro-122. 240 HLWAU42 695737 250 220-393 513 HLWAU42 840855 263 1751-1924 526 241 HGCAC19 851527 251 317-346 514 14q24.3 104311, 109150, 182600, 245200, 601208 HGCAC19 842540 264 315-344 527 HGCAC19 801999 265 317-346 528 242 HEQBJ01 876546 252 2603-2662 515 HEQBJ01 861786 266 2603-2662 529 HEQBJ01 834633 267 505-564 530 243 HBJHT01 587262 253 200-265 516 HBJHT01 580026 268 193-336 531 244 HE8FD92 901142 254 2141-2272 517 HE8FD92 888274 269 157-288 532 HE8FD92 869847 270 2268-2399 533 HE8FD92 856544 271   2-1414 534 Asp-11 to Tyr-16. HE8FD92 843825 272 1074-1205 535 245 HBDAB91 864374 255 671-760 518 Lys-21 to Gln-29. HBDAB91 789532 273 351-440 536 Lys-21 to Gln-29.

TABLE 1B.2 Gene cDNA Tissue DistributionLibrary Code: Count No: Clone ID Contig ID: SEQ ID NO: X (see Table 4 for Library Codes) 1 H6EDM64 841331 11 AR277: 22, AR060: 22, AR055: 21, AR283: 18, AR282: 18, AR104: 16, AR185: 16, AR089: 16, AR299: 16, AR219: 14, AR240: 14, AR316: 13, AR096: 12, AR218: 12, AR039: 11, AR300: 11, AR313: 11, H0333: 6, H0556: 5, H0255: 5, H0618: 4, L0783: 4, S0358: 3, H0549: 3, S0222: 3, H0318: 3, H0052: 3, H0553: 3, H0135: 3, L0769: 3, L3905: 3, H0547: 3, H0521: 3, H0555: 3, H0423: 3, H0716: 2, H0341: 2, H0402: 2, H0592: 2, H0253: 2, S0474: 2, H0620: 2, H0181: 2, H0617: 2, H0059: 2, L0761: 2, L0764: 2, L0809: 2, L5622: 2, H0520: 2, H0682: 2, S0330: 2, H0436: 2, L0751: 2, L0747: 2, L0750: 2, L0755: 2, S0436: 2, L0596: 2, L0601: 2, H0624: 1, H0686: 1, H0295: 1, T0049: 1, H0657: 1, H0656: 1, H0484: 1, H0483: 1, S0356: 1, S0442: 1, S0354: 1, S0360: 1, S0410: 1, H0729: 1, H0742: 1, S0045: 1, S0476: 1, H0619: 1, S0300: 1, L0717: 1, S0220: 1, H0370: 1, H0455: 1, H0586: 1, H0587: 1, H0559: 1, L0623: 1, T0082: 1, H0581: 1, H0183: 1, H0205: 1, H0327: 1, H0050: 1, H0687: 1, H0615: 1, T0006: 1, H0424: 1, H0213: 1, H0606: 1, H0166: 1, S0366: 1, H0090: 1, H0087: 1, H0264: 1, H0488: 1, H0413: 1, H0100: 1, H0625: 1, H0561: 1, H0130: 1, H0633: 1, H0647: 1, S0426: 1, H0529: 1, L0371: 1, L0796: 1, L0637: 1, L5566: 1, L0648: 1, L0364: 1, L0649: 1, L0774: 1, L0375: 1, L0378: 1, L0659: 1, L0636: 1, L5623: 1, L4501: 1, L0663: 1, H0693: 1, H0593: 1, S0126: 1, H0522: 1, S0027: 1, S0028: 1, L0740: 1, L0780: 1, L0758: 1, H0445: 1, S0011: 1, H0136: 1, S0196: 1 and H0352: 1. 2 H6EEU40 757048 12 AR277: 63, AR283: 52, AR219: 45, AR282: 44, AR104: 43, AR218: 41, AR316: 39, AR089: 37, AR313: 37, AR299: 35, AR055: 33, AR240: 33, AR096: 30, AR185: 29, AR300: 28, AR039: 27, AR060: 27, L0741: 8, H0677: 7, L0439: 6, H0052: 5, H0494: 5, L0747: 5, S0007: 4, H0543: 4, H0009: 3, L0771: 3, L0775: 3, L0663: 3, L0665: 3, L0438: 3, H0547: 3, H0521: 3, H0436: 3, L0742: 3, L0748: 3, L0751: 3, S0436: 3, H0556: 2, H0255: 2, S0420: 2, S0358: 2, S0046: 2, L0717: 2, S0222: 2, H0333: 2, H0559: 2, H0318: 2, H0581: 2, H0545: 2, H0620: 2, H0024: 2, H0266: 2, H0617: 2, H0529: 2, L0662: 2, L0653: 2, L0659: 2, L0809: 2, L0664: 2, H0690: 2, H0555: 2, L0743: 2, L0755: 2, L0757: 2, L0759: 2, L0588: 2, H0352: 2, H0624: 1, H0685: 1, H0740: 1, H0295: 1, S0134: 1, H0583: 1, H0656: 1, H0341: 1, S0212: 1, H0484: 1, L3659: 1, S0418: 1, S0356: 1, S0442: 1, S0410: 1, H0729: 1, H0735: 1, H0339: 1, H0619: 1, S0278: 1, H0257: 1, H0069: 1, H0744: 1, H0327: 1, H0023: 1, S0051: 1, T0010: 1, H0031: 1, H0181: 1, H0032: 1, H0169: 1, S0364: 1, H0135: 1, H0163: 1, H0090: 1, H0063: 1, H0087: 1, H0551: 1, H0264: 1, H0488: 1, H0623: 1, H0100: 1, S0438: 1, S0440: 1, L0369: 1, L0770: 1, L0769: 1, L5565: 1, L0761: 1, L0667: 1, L0772: 1, L0641: 1, L0644: 1, L0764: 1, L0773: 1, L0363: 1, L0768: 1, L0794: 1, L0766: 1, L0381: 1, L0803: 1, L0774: 1, L0375: 1, L0806: 1, L0512: 1, L0517: 1, L0666: 1, H0144: 1, H0702: 1, S0148: 1, L0352: 1, H0519: 1, H0593: 1, H0435: 1, H0658: 1, H0539: 1, S0406: 1, H0478: 1, H0631: 1, S0028: 1, S0206: 1, L0744: 1, L0740: 1, L0745: 1, L0749: 1, L0750: 1, L0758: 1, H0445: 1, S0434: 1, L0594: 1, S0194: 1, H0542: 1 and H0423: 1. 3 HACBJ56 847112 13 AR251: 7, AR310: 6, AR265: 6, AR053: 6, AR060: 6, AR182: 6, AR055: 6, AR312: 5, AR309: 5, AR273: 5, AR282: 5, AR061: 5, AR206: 5, AR241: 5, AR194: 5, AR186: 5, AR270: 4, AR213: 4, AR052: 4, AR266: 4, AR218: 4, AR089: 4, AR274: 4, AR253: 4, AR269: 4, AR291: 4, AR248: 4, AR296: 4, AR183: 4, AR240: 4, AR104: 4, AR293: 4, AR205: 4, AR284: 4, AR289: 3, AR313: 3, AR184: 3, AR299: 3, AR247: 3, AR185: 3, AR316: 3, AR231: 3, AR298: 3, AR033: 3, AR243: 3, AR268: 3, AR290: 3, AR283: 3, AR295: 3, AR300: 3, AR246: 3, AR277: 3, AR232: 3, AR175: 3, AR096: 3, AR219: 3, AR177: 3, AR234: 3, AR233: 3, AR275: 3, AR237: 3, AR238: 3, AR285: 3, AR227: 3, AR202: 3, AR263: 3, AR292: 3, AR204: 2, AR286: 2, AR314: 2, AR267: 2, AR280: 2, AR229: 2, AR258: 2, AR039: 2, AR294: 2, AR256: 2, AR259: 2, AR281: 1, AR315: 1, AR226: 1, AR244: 1, AR249: 1, H0661: 1, S0045: 1, H0550: 1, S0280: 1, S0010: 1, H0028: 1, L0764: 1, L0803: 1, L0805: 1, L0665: 1, S0053: 1, H0670: 1, L0748: 1, L0731: 1 and L0581: 1. 4 HACBS22 847113 14 L0439: 9, L0751: 7, L0766: 6, L0361: 6, H0052: 5, S0002: 5, L0769: 5, L0777: 5, L0770: 4, L0771: 4, L0748: 4, L0754: 4, L0758: 4, L0759: 4, L0596: 4, S0474: 3, S0051: 3, S0142: 3, L0662: 3, L0747: 3, H0170: 2, H0580: 2, S0046: 2, H0619: 2, L0717: 2, H0550: 2, S0280: 2, H0039: 2, S0422: 2, L0794: 2, L0775: 2, L0805: 2, L0655: 2, L5623: 2, L0666: 2, L0665: 2, L0438: 2, H0539: 2, L0742: 2, L0749: 2, L0779: 2, L0731: 2, L0757: 2, L0581: 2, H0171: 1, H0265: 1, H0556: 1, H0686: 1, S0040: 1, H0650: 1, H0661: 1, H0663: 1, H0306: 1, S0420: 1, S0356: 1, S0442: 1, S0354: 1, L3646: 1, H0637: 1, S0222: 1, H0431: 1, H0586: 1, H0492: 1, H0486: 1, L3655: 1, H0156: 1, H0042: 1, H0253: 1, H0545: 1, H0563: 1, H0123: 1, H0014: 1, H0622: 1, T0023: 1, H0033: 1, H0213: 1, H0135: 1, H0038: 1, H0063: 1, S0038: 1, T0042: 1, H0560: 1, H0561: 1, S0372: 1, S0450: 1, S0344: 1, H0538: 1, S0426: 1, L0762: 1, L0637: 1, L3905: 1, L5566: 1, L0643: 1, L0650: 1, L0774: 1, L0375: 1, L0776: 1, L0807: 1, L0663: 1, L2263: 1, L3824: 1, S0126: 1, H0689: 1, H0658: 1, H0754: 1, S0174: 1, S0406: 1, L0743: 1, S0031: 1, S0436: 1, H0668: 1, L3378: 1 and H0506: 1. 5 HACBT91 789939 15 AR283: 41, AR219: 39, AR277: 38, AR218: 33, AR055: 29, AR316: 28, AR039: 25, AR104: 22, AR299: 22, AR096: 20, AR089: 20, AR185: 19, AR240: 19, AR282: 18, AR060: 17, AR300: 16, AR313: 16, L0665: 5, L0743: 3, H0341: 2, L0761: 2, L0756: 2, S0356: 1, H0734: 1, S0280: 1, T0048: 1, H0271: 1, S0440: 1, H0641: 1, H0646: 1, L0770: 1, L0637: 1, L0800: 1, L0773: 1, L0648: 1, L0662: 1, L0768: 1, L0766: 1, L0649: 1, L0375: 1, L0784: 1, L0806: 1, L0655: 1, L0809: 1, H0672: 1, S0406: 1, L0747: 1, L0749: 1 and L0750: 1. 6 HADDJ13 827273 16 H0427: 1 7 HADMA77 783049 17 AR104: 16, AR039: 10, AR277: 9, AR089: 9, AR240: 9, AR055: 9, AR300: 8, AR218: 7, AR299: 7, AR283: 7, AR060: 7, AR282: 7, AR316: 6, AR219: 6, AR096: 5, AR185: 5, AR313: 4, L0439: 15, S0222: 4, L0157: 4, L0769: 4, L0438: 3, L0745: 3, L0731: 3, L0758: 3, L0599: 3, H0443: 2, H0441: 2, S0010: 2, L0662: 2, L0744: 2, L0748: 2, L0750: 2, L0756: 2, L0777: 2, H0583: 1, L0005: 1, S0354: 1, H0675: 1, S0408: 1, H0619: 1, H0369: 1, H0574: 1, H0486: 1, H0390: 1, S0346: 1, H0309: 1, H0597: 1, T0003: 1, H0024: 1, S6028: 1, H0028: 1, T0006: 1, H0628: 1, H0135: 1, H0551: 1, S0438: 1, L0520: 1, L0768: 1, L0776: 1, L0559: 1, L0659: 1, L0384: 1, L0809: 1, H0144: 1, H0547: 1, L0746: 1, L0747: 1, L0757: 1 and S0434: 1. 8 HADMB15 847116 18 AR104: 19, AR218: 19, AR219: 16, AR089: 11, AR313: 8, AR055: 8, AR060: 7, AR299: 6, AR282: 5, AR300: 5, AR039: 5, AR240: 5, AR316: 5, AR185: 5, AR277: 4, AR283: 4, AR096: 3, L0595: 2, L0442: 1, L0005: 1, L3653: 1, H0390: 1, H0081: 1, H0024: 1, L0770: 1, L5566: 1, L0651: 1, L0565: 1, L0439: 1, L0747: 1, L0752: 1, H0445: 1, L0592: 1 and L0599: 1. 9 HAGBQ12 722205 19 AR060: 7, AR055: 6, AR104: 5, AR185: 5, AR089: 4, AR299: 4, AR277: 4, AR300: 4, AR283: 4, AR313: 3, AR316: 3, AR240: 3, AR039: 3, AR096: 3, AR282: 2, AR218: 2, AR219: 1, L0754: 4, L0805: 2, L0777: 2, L0755: 2, S0010: 1, H0049: 1, L0163: 1, L0771: 1, L0775: 1 and L0776: 1. 10 HAGCC87 638587 20 AR313: 17, AR039: 14, AR277: 10, AR104: 10, AR089: 9, AR300: 9, AR096: 9, AR299: 8, AR185: 7, AR055: 6, AR060: 6, AR218: 6, AR240: 6, AR316: 6, AR282: 4, AR283: 4, AR219: 3, L0439: 4, L0519: 3, S0010: 2, T0010: 1, L0809: 1, H0682: 1, S0404: 1, S0406: 1, H0436: 1 and L0756: 1. 11 HAGFJ67 861680 21 AR219: 15, AR218: 14, AR104: 10, AR060: 9, AR089: 9, AR055: 8, AR299: 8, AR240: 7, AR096: 7, AR039: 7, AR300: 7, AR185: 7, AR316: 6, AR282: 6, AR283: 6, AR313: 6, AR277: 3, L0777: 6, L0749: 5, L0804: 3, L0439: 3, L0754: 3, L0766: 2, L0788: 2, L0438: 2, L0747: 2, H0265: 1, H0455: 1, S0010: 1, L0655: 1, L0666: 1, S0053: 1, S0374: 1, L0352: 1, L0751: 1, L0756: 1, L0755: 1, L0731: 1, L0757: 1, L0758: 1, L0759: 1, L0599: 1 and L0604: 1. 12 HAGFS57 847120 22 AR055: 7, AR104: 6, AR060: 5, AR277: 4, AR300: 3, AR299: 3, AR096: 3, AR316: 3, AR039: 2, AR185: 2, AR089: 2, AR283: 2, AR218: 2, AR219: 1, AR313: 1, AR240: 1, L0438: 6, L0439: 4, S0360: 3, S0422: 3, H0547: 3, L0747: 3, L0005: 2, S0222: 2, S0002: 2, L0664: 2, L0754: 2, S0434: 2, H0506: 2, H0170: 1, H0171: 1, S0116: 1, S0212: 1, H0580: 1, H0749: 1, H0455: 1, L3655: 1, H0069: 1, H0098: 1, S0010: 1, L0105: 1, H0581: 1, H0263: 1, H0009: 1, L0471: 1, H0099: 1, S0003: 1, H0039: 1, S0036: 1, H0090: 1, H0591: 1, S0426: 1, L0794: 1, L0776: 1, L5622: 1, S0052: 1, H0144: 1, H0682: 1, H0659: 1, H0521: 1, H0555: 1, L0756: 1, H0445: 1 and S0452: 1. 13 HAGHN57 773286 23 AR313: 12, AR316: 11, AR218: 11, AR185: 11, AR039: 10, AR219: 10, AR299: 10, AR060: 9, AR055: 8, AR277: 8, AR282: 8, AR096: 7, AR089: 7, AR300: 7, AR240: 6, AR104: 6, AR283: 4, H0521: 5, L0777: 5, S0376: 4, H0733: 3, H0156: 3, H0519: 3, H0436: 3, L0731: 3, H0656: 2, H0580: 2, H0747: 2, L3816: 2, H0036: 2, L0471: 2, H0090: 2, H0040: 2, H0551: 2, H0494: 2, S0438: 2, S0440: 2, H0529: 2, L0809: 2, H0144: 2, S0374: 2, H0593: 2, H0170: 1, L3643: 1, H0583: 1, H0650: 1, S0418: 1, S0358: 1, S0444: 1, L3645: 1, H0741: 1, H0734: 1, S0045: 1, S0476: 1, H0619: 1, H0586: 1, H0643: 1, H0632: 1, H0486: 1, S0280: 1, H0590: 1, S0010: 1, S0346: 1, H0581: 1, H0231: 1, H0046: 1, H0123: 1, S6028: 1, H0687: 1, S0003: 1, S0214: 1, H0252: 1, H0615: 1, H0212: 1, L0455: 1, S0366: 1, H0163: 1, H0038: 1, H0634: 1, T0067: 1, L0475: 1, H0560: 1, H0561: 1, S0464: 1, H0646: 1, S0426: 1, H0026: 1, L0790: 1, H0520: 1, H0435: 1, S0328: 1, H0539: 1, H0704: 1, S0027: 1, L0439: 1, L0750: 1, L0756: 1, L0757: 1, S0434: 1, L0581: 1, L0595: 1, H0543: 1 and H0423: 1. 14 HAGHR18 655435 24 AR052: 6, AR055: 6, AR247: 6, AR061: 6, AR053: 6, AR060: 5, AR182: 5, AR263: 5, AR310: 5, AR312: 4, AR251: 4, AR033: 4, AR244: 4, AR293: 4, AR282: 4, AR269: 3, AR185: 3, AR270: 3, AR298: 3, AR089: 3, AR253: 3, AR296: 3, AR104: 3, AR232: 3, AR299: 3, AR285: 3, AR198: 3, AR286: 3, AR184: 3, AR237: 3, AR277: 3, AR295: 3, AR300: 3, AR213: 3, AR284: 2, AR283: 2, AR267: 2, AR266: 2, AR290: 2, AR268: 2, AR289: 2, AR313: 2, AR316: 2, AR294: 2, AR186: 2, AR096: 2, AR183: 2, AR233: 2, AR240: 2, AR229: 2, AR218: 2, AR177: 2, AR259: 2, AR246: 2, AR248: 2, AR175: 2, AR292: 2, AR309: 2, AR265: 2, AR226: 1, AR039: 1, AR234: 1, AR179: 1, AR258: 1, AR219: 1, AR231: 1, AR238: 1, L0717: 1 and S0346: 1. 15 HAJAA47 534670 25 H0560: 1, H0561: 1 and H0542: 1. 16 HAJAY92 845601 26 AR060: 184, AR055: 136, AR185: 131, AR299: 118, AR283: 100, AR300: 99, AR277: 94, AR089: 94, AR104: 84, AR282: 79, AR039: 68, AR316: 65, AR240: 60, AR096: 54, AR218: 35, AR219: 33, AR313: 33, H0561: 1 and L0758: 1. 17 HAJBV67 866415 27 AR039: 11, AR219: 10, AR316: 9, AR218: 9, AR089: 9, AR270: 8, AR282: 8, AR283: 8, AR269: 8, AR248: 7, AR299: 7, AR183: 7, AR309: 7, AR277: 7, AR096: 7, AR104: 7, AR313: 7, AR281: 7, AR265: 6, AR249: 6, AR253: 6, AR315: 6, AR300: 6, AR290: 6, AR292: 6, AR202: 6, AR312: 6, AR280: 6, AR175: 6, AR231: 5, AR182: 5, AR185: 5, AR268: 5, AR060: 5, AR294: 5, AR194: 5, AR238: 5, AR247: 4, AR243: 4, AR053: 4, AR267: 4, AR295: 4, AR291: 4, AR055: 4, AR285: 4, AR213: 4, AR052: 4, AR184: 4, AR293: 4, AR296: 3, AR240: 3, AR033: 3, AR310: 3, AR314: 3, AR275: 3, AR246: 3, AR205: 3, AR286: 3, AR271: 3, AR234: 3, AR192: 3, AR298: 3, AR263: 3, AR232: 3, AR256: 3, AR251: 3, AR259: 2, AR284: 2, AR229: 2, AR289: 2, AR226: 2, AR274: 2, AR237: 2, AR258: 2, AR179: 2, AR177: 2, AR233: 2, AR273: 2, AR227: 2, AR204: 2, AR186: 1, AR061: 1, AR241: 1, L0754: 9, S0444: 6, S0442: 5, S0358: 5, H0622: 5, H0624: 4, H0040: 4, L0659: 4, H0144: 4, H0521: 4, H0171: 3, L3499: 3, L2630: 3, H0046: 3, H0658: 3, H0555: 3, H0436: 3, L0758: 3, S0434: 3, H0543: 3, S0418: 2, S0360: 2, S0222: 2, L2499: 2, H0013: 2, H0156: 2, H0575: 2, H0615: 2, H0674: 2, H0616: 2, H0551: 2, H0412: 2, H0623: 2, S0440: 2, H0647: 2, S0422: 2, H0529: 2, L0666: 2, L2263: 2, S0374: 2, S0380: 2, S0146: 2, L0740: 2, L0731: 2, L0759: 2, S0436: 2, L0362: 2, H0556: 1, L3644: 1, S0114: 1, T0049: 1, L0002: 1, L2910: 1, S0282: 1, L2300: 1, S0356: 1, S0354: 1, S0408: 1, S0410: 1, L3709: 1, H0637: 1, H0742: 1, H0722: 1, S0046: 1, S0132: 1, S0300: 1, L2744: 1, L0717: 1, H0411: 1, H0431: 1, H0586: 1, H0587: 1, L2491: 1, L2647: 1, H0036: 1, H0004: 1, S0010: 1, H0318: 1, H0581: 1, H0251: 1, H0596: 1, L0471: 1, H0024: 1, H0014: 1, H0375: 1, H0266: 1, S0003: 1, S0214: 1, H0688: 1, T0023: 1, H0553: 1, L0055: 1, H0032: 1, S0036: 1, H0090: 1, H0591: 1, H0038: 1, T0067: 1, H0477: 1, H0488: 1, H0059: 1, H0561: 1, L0369: 1, L3905: 1, L0662: 1, L0766: 1, L0388: 1, L0774: 1, L0775: 1, L0606: 1, L0661: 1, L0526: 1, L0809: 1, L0665: 1, L2653: 1, L3665: 1, L3811: 1, H0519: 1, S0126: 1, H0683: 1, H0684: 1, H0659: 1, H0672: 1, H0710: 1, H0522: 1, S3014: 1, S0028: 1, L0752: 1, H0595: 1, S0394: 1, L0596: 1, L0589: 1, L0485: 1, L0595: 1, H0667: 1, S0242: 1, S0194: 1, H0423: 1, H0422: 1, S0384: 1, H0506: 1 and H0352: 1. 18 HAQBG57 837545 28 H0295: 6, H0255: 2, H0392: 1, H0587: 1, H0333: 1, H0545: 1, H0328: 1, H0616: 1, S0142: 1, H0529: 1, L0659: 1, L0783: 1, L0528: 1, H0547: 1, S0136: 1, S0390: 1, L0754: 1, L0747: 1 and L0752: 1. 19 HARAE26 560598 29 AR283: 497, AR055: 181, AR218: 59, AR219: 57, AR277: 46, AR316: 43, AR240: 38, AR096: 37, AR104: 36, AR313: 35, AR039: 35, AR089: 34, AR282: 30, AR185: 28, AR299: 26, AR060: 23, AR300: 23, T0082: 1 20 HATCD80 826098 30 AR316: 50, AR055: 4, AR277: 3, AR060: 3, AR300: 3, AR282: 3, AR283: 2, AR218: 2, AR039: 1, AR104: 1, AR089: 1, AR240: 1, AR299: 1, AR185: 1, H0156: 1 and H0038: 1. 21 HBAGD86 838799 31 AR219: 7, AR218: 4, AR313: 4, AR104: 4, AR039: 3, AR299: 3, AR282: 2, AR300: 2, AR096: 2, AR316: 2, AR277: 1, AR240: 1, AR089: 1, L0809: 4, L0766: 3, L0439: 3, H0624: 2, H0411: 2, L0794: 2, L0749: 2, L0756: 2, L0005: 1, L3649: 1, S0476: 1, H0599: 1, L0471: 1, S0051: 1, T0010: 1, H0266: 1, S0150: 1, S0422: 1, L0637: 1, L0765: 1, L0803: 1, L0783: 1, L5622: 1, H0144: 1, H0672: 1, S0392: 1, L0748: 1, L0754: 1, L0779: 1, L0777: 1, L0731: 1 and L0759: 1. 22 HBGBC29 691473 32 AR299: 5, AR218: 5, AR313: 4, AR300: 4, AR055: 4, AR060: 4, AR277: 3, AR316: 3, AR089: 3, AR185: 3, AR096: 3, AR039: 3, AR219: 3, AR104: 3, AR240: 3, AR282: 2, AR283: 2, L0731: 20, L0747: 7, L0794: 6, L0764: 4, L0803: 4, L0759: 4, L0662: 3, L0774: 3, L0749: 3, L0756: 3, S0436: 3, S0360: 2, H0156: 2, H0046: 2, H0181: 2, L0766: 2, L0659: 2, L0809: 2, L0438: 2, S0126: 2, H0658: 2, L0439: 2, L0754: 2, L0777: 2, L0755: 2, L0757: 2, L0604: 2, S0242: 2, S0442: 1, S0376: 1, S0408: 1, L0717: 1, H0270: 1, H0263: 1, H0597: 1, H0123: 1, H0617: 1, H0551: 1, S0440: 1, H0647: 1, L0770: 1, L0769: 1, L0638: 1, L0775: 1, L0651: 1, L0527: 1, L0526: 1, L0789: 1, L0666: 1, L0665: 1, H0547: 1, H0435: 1, H0648: 1, S0330: 1, S0406: 1, H0627: 1, L0750: 1, L0780: 1, L0752: 1, L0758: 1, L0366: 1 and H0293: 1. 23 HBHAA05 603174 33 AR313: 74, AR039: 45, AR299: 34, AR089: 33, AR185: 31, AR277: 29, AR096: 26, AR300: 26, AR240: 22, AR316: 20, AR218: 17, AR060: 15, AR219: 14, AR104: 14, AR282: 11, AR055: 9, AR283: 6, S0029: 1 24 HBHAA81 846465 34 AR289: 34, AR291: 33, AR283: 32, AR055: 32, AR294: 26, AR266: 26, AR286: 26, AR256: 23, AR285: 21, AR293: 19, AR259: 17, AR295: 16, AR292: 15, AR298: 14, AR258: 14, AR296: 12, AR284: 11, AR104: 10, AR033: 9, AR186: 9, AR202: 7, AR206: 7, AR246: 7, AR204: 7, AR241: 6, AR194: 5, AR198: 4, AR244: 4, AR251: 4, AR060: 4, AR061: 4, AR282: 4, AR052: 4, AR053: 4, AR205: 4, AR309: 4, AR316: 3, AR182: 3, AR312: 3, AR192: 3, AR273: 3, AR229: 3, AR183: 3, AR310: 3, AR271: 3, AR213: 3, AR248: 3, AR270: 3, AR277: 2, AR185: 2, AR275: 2, AR299: 2, AR269: 2, AR300: 2, AR247: 2, AR267: 2, AR175: 2, AR089: 2, AR313: 2, AR265: 2, AR268: 2, AR237: 2, AR096: 1, AR232: 1, AR039: 1, AR240: 1, AR179: 1, AR231: 1, AR234: 1, H0599: 8, S0366: 7, L0485: 6, H0733: 5, H0734: 5, L0769: 5, H0735: 4, H0729: 3, H0728: 3, H0619: 2, H0706: 2, L0661: 2, L0756: 2, L0759: 2, S0282: 1, S0029: 1, S0222: 1, L0622: 1, H0122: 1, S0010: 1, H0196: 1, H0012: 1, H0200: 1, H0373: 1, S6028: 1, S0364: 1, S0036: 1, S0294: 1, L0770: 1, L0638: 1, L5565: 1, L0657: 1, L0809: 1, L0789: 1, L0791: 1, L0438: 1, L0439: 1, L0750: 1, L0777: 1, S0260: 1, L0604: 1 and S0460: 1. 25 HBJAB02 837309 35 AR282: 3, AR277: 1, AR039: 1, AR316: 1, S0434: 5, L0794: 3, H0255: 2, H0318: 2, H0251: 2, L0764: 2, L0628: 2, L0809: 2, L0665: 2, H0658: 2, S0406: 2, L0361: 2, H0265: 1, H0685: 1, H0657: 1, H0483: 1, S0420: 1, S0442: 1, S0358: 1, H0729: 1, H0734: 1, S0132: 1, S0222: 1, T0082: 1, H0150: 1, H0083: 1, S0214: 1, H0252: 1, H0628: 1, T0041: 1, S0344: 1, H0529: 1, L0520: 1, L0535: 1, L0662: 1, L0387: 1, L0375: 1, L0518: 1, L0666: 1, L0663: 1, H0726: 1, H0519: 1, H0670: 1, H0660: 1, L0602: 1, L0747: 1, L0777: 1, L0601: 1, S0276: 1, H0423: 1 and H0422: 1. 26 HBJAC40 841235 36 AR104: 23, AR060: 6, AR055: 6, AR283: 5, AR185: 5, AR282: 4, AR313: 4, AR299: 4, AR316: 4, AR277: 3, AR096: 3, AR240: 3, AR219: 2, AR089: 2, AR300: 2, AR039: 2, AR218: 2, L0439: 18, H0052: 12, L0741: 8, L0438: 6, S0051: 5, H0556: 4, L0769: 4, L0774: 4, S0474: 3, H0622: 3, S0036: 3, L3905: 3, H0261: 2, H0318: 2, H0194: 2, L0471: 2, H0538: 2, L0749: 2, L0757: 2, L0758: 2, S0436: 2, L0593: 2, H0624: 1, H0265: 1, S0342: 1, H0717: 1, H0650: 1, H0657: 1, S0212: 1, S0282: 1, H0730: 1, S0045: 1, S0476: 1, H0619: 1, S0222: 1, H0455: 1, H0559: 1, H0075: 1, H0253: 1, H0251: 1, H0544: 1, L0158: 1, H0012: 1, S0050: 1, L0163: 1, H0083: 1, H0594: 1, H0615: 1, T0006: 1, H0708: 1, H0087: 1, H0056: 1, S0038: 1, H0494: 1, S0450: 1, S0144: 1, L0770: 1, L4747: 1, L0639: 1, L0761: 1, L0775: 1, L0805: 1, L0635: 1, L5622: 1, L0788: 1, S0428: 1, S0044: 1, L0612: 1, L0742: 1, L0748: 1, L0779: 1, L0777: 1, S0011: 1 and H0136: 1. 27 HBJCR46 815649 37 L0794: 11, L0803: 10, L0779: 10, H0038: 9, L0777: 9, L0758: 9, S0358: 6, L0809: 5, S0408: 4, H0616: 4, L0748: 4, L0439: 4, L0591: 4, S0282: 3, L0789: 3, L0666: 3, L0438: 3, L0756: 3, H0036: 2, H0196: 2, H0046: 2, H0154: 2, L0163: 2, H0213: 2, S0036: 2, L0804: 2, L0774: 2, L0655: 2, L0656: 2, S0374: 2, S0126: 2, S0328: 2, S0152: 2, H0521: 2, S0406: 2, L0731: 2, L0588: 2, L0485: 2, S0026: 2, H0543: 2, H0170: 1, H0171: 1, H0713: 1, S6024: 1, H0650: 1, H0656: 1, S0116: 1, H0341: 1, H0638: 1, S0442: 1, S0354: 1, H0318: 1, H0581: 1, H0230: 1, H0597: 1, H0544: 1, H0178: 1, H0123: 1, H0050: 1, S0050: 1, H0014: 1, S6028: 1, H0266: 1, S0003: 1, H0033: 1, H0032: 1, H0673: 1, H0598: 1, H0163: 1, H0040: 1, H0551: 1, H0623: 1, H0100: 1, T0041: 1, H0561: 1, S0438: 1, H0641: 1, S0344: 1, S0002: 1, S0426: 1, L0769: 1, L0800: 1, L0641: 1, L0766: 1, L0775: 1, L0375: 1, L0653: 1, L0634: 1, L0659: 1, L0783: 1, L0787: 1, L0663: 1, L0664: 1, L0665: 1, H0725: 1, H0670: 1, H0522: 1, H0436: 1, H0540: 1, S0027: 1, L0740: 1, L0751: 1, L0747: 1, L0749: 1, L0786: 1, L0780: 1, L0752: 1, L0757: 1, L0608: 1, L0604: 1, S0192: 1 and S0276: 1. 28 HBJDW56 520401 38 AR055: 8, AR060: 7, AR282: 6, AR104: 5, AR313: 5, AR185: 5, AR300: 4, AR089: 4, AR299: 4, AR240: 4, AR039: 4, AR219: 4, AR316: 3, AR096: 3, AR283: 3, AR218: 3, AR277: 2, H0318: 1 29 HBJEL16 847030 39 H0046: 2, H0009: 2, H0090: 2, H0494: 2, L0438: 2, H0547: 2, H0521: 2, L0439: 2, L0777: 2, H0543: 2, H0556: 1, S0342: 1, S0045: 1, H0619: 1, H0632: 1, H0013: 1, H0156: 1, L0021: 1, H0575: 1, H0318: 1, S0003: 1, L0483: 1, H0628: 1, H0623: 1, H0561: 1, L0761: 1, L0803: 1, L0804: 1, L0659: 1, L0382: 1, H0144: 1, H0539: 1, S0152: 1, H0478: 1, H0631: 1, L0741: 1, L0740: 1 and L0591: 1. 30 HBJFK45 531919 40 AR282: 3, AR055: 2, AR060: 2, AR219: 2, AR185: 2, AR300: 1, AR039: 1, AR283: 1, AR218: 1, H0318: 1 and L0766: 1. 31 HBJKD16 853358 41 AR172: 63, AR171: 62, AR215: 61, AR274: 50, AR216: 48, AR213: 43, AR214: 41, AR272: 41, AR169: 41, AR224: 37, AR225: 37, AR217: 37, AR254: 36, AR205: 36, AR170: 35, AR243: 35, AR168: 35, AR247: 34, AR245: 32, AR312: 32, AR221: 32, AR212: 31, AR161: 29, AR222: 28, AR162: 28, AR311: 27, AR308: 27, AR163: 26, AR275: 26, AR165: 25, AR164: 24, AR313: 23, AR053: 23, AR166: 23, AR223: 21, AR039: 20, AR089: 20, AR309: 19, AR096: 19, AR242: 18, AR253: 18, AR240: 17, AR289: 16, AR266: 16, AR283: 16, AR263: 16, AR193: 16, AR316: 16, AR264: 16, AR204: 16, AR250: 15, AR282: 15, AR201: 15, AR277: 15, AR207: 14, AR291: 14, AR246: 14, AR200: 13, AR198: 13, AR271: 12, AR299: 12, AR300: 12, AR195: 12, AR185: 12, AR104: 12, AR290: 11, AR192: 11, AR173: 11, AR255: 11, AR257: 11, AR060: 11, AR197: 11, AR252: 10, AR180: 10, AR297: 10, AR179: 10, AR210: 10, AR061: 10, AR181: 9, AR296: 9, AR199: 9, AR270: 9, AR269: 9, AR178: 9, AR183: 9, AR268: 8, AR055: 8, AR177: 8, AR262: 8, AR236: 8, AR288: 8, AR211: 8, AR188: 7, AR267: 7, AR293: 7, AR219: 7, AR285: 7, AR256: 7, AR294: 7, AR174: 7, AR176: 7, AR189: 7, AR033: 7, AR261: 7, AR218: 7, AR287: 6, AR175: 6, AR196: 6, AR231: 6, AR203: 6, AR286: 5, AR235: 5, AR190: 5, AR230: 5, AR234: 5, AR191: 5, AR182: 5, AR260: 5, AR258: 4, AR295: 4, AR237: 4, AR233: 4, AR229: 4, AR238: 4, AR239: 3, AR226: 3, AR232: 2, AR227: 2, AR228: 2, L0766: 9, L0439: 9, L0747: 6, L2528: 5, L0777: 5, H0673: 4, L0438: 4, L0758: 4, L0362: 4, S0116: 3, L0748: 3, L0752: 3, H0445: 3, H0156: 2, T0010: 2, H0615: 2, H0038: 2, H0616: 2, H0264: 2, H0646: 2, L0761: 2, L0776: 2, L0750: 2, L0779: 2, S0436: 2, L0593: 2, S0242: 2, H0222: 1, H0740: 1, H0657: 1, H0661: 1, H0663: 1, L2293: 1, H0589: 1, S0444: 1, H0340: 1, L3646: 1, H0580: 1, H0749: 1, H0393: 1, H0549: 1, S0222: 1, H0574: 1, H0486: 1, H0013: 1, H0069: 1, L0021: 1, S0010: 1, H0318: 1, S0474: 1, H0046: 1, L0471: 1, H0090: 1, L0638: 1, L0646: 1, L0764: 1, L0521: 1, L0364: 1, L0774: 1, L0659: 1, L0543: 1, L5622: 1, L0792: 1, L0666: 1, L0664: 1, L0665: 1, S0428: 1, L2657: 1, L2652: 1, L3663: 1, L2262: 1, H0435: 1, L3832: 1, L0741: 1, L0749: 1, S0434: 1, L0588: 1, H0422: 1, L0698: 1 and L2359: 1. 32 HBMUH74 866160 42 AR218: 12, AR055: 8, AR060: 7, AR104: 7, AR219: 5, AR240: 5, AR299: 5, AR096: 4, AR316: 4, AR300: 4, AR039: 4, AR089: 3, AR283: 3, AR185: 3, AR313: 3, AR282: 2, AR277: 2, L0754: 3, L0777: 3, L0439: 2, S0116: 1, H0341: 1, H0661: 1, H0038: 1, H0412: 1, L0761: 1, L0667: 1, L0764: 1, L0788: 1, H0435: 1, L0749: 1, L0779: 1 and L0758: 1. 33 HBQAB79 810542 43 AR055: 7, AR218: 7, AR060: 6, AR039: 6, AR300: 5, AR185: 5, AR313: 5, AR240: 4, AR299: 4, AR089: 4, AR096: 3, AR316: 3, AR283: 3, AR104: 2, AR219: 2, AR277: 2, AR282: 1, H0229: 1 34 HBXCM66 639039 44 AR313: 74, AR039: 52, AR299: 36, AR300: 36, AR096: 35, AR089: 32, AR277: 32, AR185: 32, AR240: 23, AR316: 22, AR218: 15, AR104: 14, AR219: 14, AR060: 13, AR282: 11, AR055: 7, AR283: 3, H0550: 2, L0523: 2, S0282: 1, S0045: 1, H0549: 1, H0052: 1 and S0038: 1. 35 HBXCX15 637542 45 S0038: 3, H0438: 1, L0363: 1 and S0053: 1. 36 HCDBO32 831942 46 AR219: 9, AR185: 8, AR055: 8, AR218: 8, AR089: 6, AR313: 6, AR283: 6, AR282: 6, AR104: 5, AR060: 5, AR316: 5, AR300: 5, AR299: 4, AR096: 4, AR240: 4, AR277: 4, AR039: 3, L0803: 7, L0766: 4, L0777: 4, L0666: 3, H0521: 3, T0115: 2, H0687: 2, L0809: 2, H0659: 2, L0754: 2, L0779: 2, L0759: 2, L3643: 1, H0341: 1, H0747: 1, H0749: 1, L3387: 1, H0351: 1, S0222: 1, H0441: 1, L3816: 1, H0013: 1, S0280: 1, H0251: 1, H0544: 1, H0123: 1, H0354: 1, H0266: 1, H0622: 1, H0090: 1, T0041: 1, H0641: 1, S0422: 1, L0371: 1, L0646: 1, L0662: 1, L0774: 1, L0805: 1, L0653: 1, L0659: 1, L0635: 1, L0526: 1, L0783: 1, L0663: 1, L0664: 1, L0665: 1, H0144: 1, T0068: 1, L3811: 1, H0519: 1, H0682: 1, S0152: 1, S0136: 1, L0744: 1, L0780: 1, L0758: 1, H0444: 1, H0445: 1, L0590: 1, L0594: 1, S0026: 1 and H0422: 1. 37 HCEDR26 771144 47 AR313: 59, AR039: 47, AR277: 33, AR299: 28, AR185: 25, AR096: 23, AR089: 23, AR300: 20, AR219: 19, AR240: 17, AR316: 16, AR104: 15, AR282: 13, AR218: 13, AR060: 13, AR283: 10, AR055: 10, H0052: 2, H0018: 1, H0264: 1 and L0700: 1. 38 HCEEE79 560609 48 H0052: 1 39 HCEFG93 745400 49 AR313: 44, AR039: 38, AR299: 23, AR185: 18, AR089: 17, AR277: 16, AR096: 15, AR300: 15, AR219: 15, AR104: 14, AR218: 12, AR316: 11, AR240: 9, AR060: 8, AR282: 6, AR055: 6, AR283: 3, H0052: 1 40 HCEFZ82 831745 50 L0748: 11, H0052: 8, L0803: 8, L0749: 8, L0770: 7, L0439: 5, L0746: 4, L0752: 4, L3811: 3, H0575: 2, H0012: 2, H0031: 2, L0768: 2, L0804: 2, L0774: 2, L0740: 2, L0747: 2, L0756: 2, L0779: 2, L0757: 2, L0758: 2, L0592: 2, L0593: 2, H0556: 1, S0420: 1, S0376: 1, H0441: 1, H0632: 1, S0010: 1, T0115: 1, H0545: 1, H0009: 1, H0620: 1, H0197: 1, H0051: 1, S0388: 1, S0051: 1, H0252: 1, H0032: 1, L0455: 1, H0591: 1, H0272: 1, L0564: 1, S0438: 1, S0344: 1, L0373: 1, L0646: 1, L0794: 1, L0766: 1, L0805: 1, L0776: 1, L0783: 1, L0809: 1, S0374: 1, H0522: 1, H0134: 1, L0780: 1, L0731: 1, L0759: 1, S0436: 1, L0597: 1, H0543: 1, H0423: 1 and L0600: 1. 41 HCFLN88 610000 51 S0410: 22, L0770: 9, L0748: 9, L0769: 7, L0776: 6, L0659: 6, H0424: 5, L0761: 5, L0731: 5, H0486: 4, L0803: 4, L0809: 4, L0666: 4, H0696: 4, L0754: 4, L0779: 4, L0758: 4, H0729: 3, H0618: 3, H0135: 3, L0637: 3, L0771: 3, L0766: 3, L0805: 3, L0665: 3, L0751: 3, H0542: 3, H0341: 2, H0402: 2, S0358: 2, S0376: 2, S0360: 2, H0747: 2, S0132: 2, L3109: 2, L0717: 2, H0592: 2, H0253: 2, S0010: 2, H0052: 2, H0545: 2, H0050: 2, H0617: 2, H0087: 2, H0551: 2, H0100: 2, H0560: 2, L0763: 2, L5565: 2, L0646: 2, L0764: 2, L0655: 2, L0663: 2, L2260: 2, S0374: 2, H0414: 2, S0406: 2, H0436: 2, L0743: 2, L0740: 2, L0749: 2, L0755: 2, L0757: 2, L0759: 2, H0445: 2, H0136: 2, H0543: 2, H0423: 2, H0352: 2, H0170: 1, H0171: 1, H0225: 1, H0713: 1, S0218: 1, L0785: 1, H0692: 1, S0212: 1, H0483: 1, H0254: 1, H0305: 1, S0356: 1, S0442: 1, S0444: 1, S0408: 1, H0619: 1, H0393: 1, H0406: 1, H0370: 1, H0249: 1, H0101: 1, H0250: 1, S0280: 1, H0599: 1, H0575: 1, H0706: 1, T0048: 1, H0318: 1, S0474: 1, H0581: 1, T0115: 1, H0009: 1, H0572: 1, H0024: 1, S0051: 1, H0271: 1, H0288: 1, T0006: 1, H0213: 1, H0553: 1, H0644: 1, S0364: 1, H0163: 1, H0090: 1, H0264: 1, H0488: 1, S0112: 1, H0494: 1, H0652: 1, S0344: 1, S0002: 1, S0426: 1, L4497: 1, L5575: 1, L3905: 1, L5566: 1, L0772: 1, L0641: 1, L0645: 1, L0773: 1, L0650: 1, L0774: 1, L0775: 1, L0378: 1, L0806: 1, L0783: 1, L5622: 1, L0790: 1, L0664: 1, L3827: 1, H0547: 1, H0519: 1, S0126: 1, H0711: 1, H0672: 1, S0330: 1, H0521: 1, S0392: 1, S0037: 1, L0742: 1, L0439: 1, L0745: 1, L0747: 1, L0750: 1, L0777: 1, S0436: 1, L0485: 1, L0608: 1, S0011: 1, H0653: 1 and H0422: 1. 42 HCHAB84 834326 52 AR313: 37, AR039: 34, AR104: 24, AR300: 24, AR277: 23, AR096: 23, AR185: 20, AR089: 20, AR299: 19, AR219: 18, AR218: 17, AR316: 16, AR240: 16, AR282: 13, AR283: 9, AR060: 8, AR055: 7, S0354: 9, S0358: 3, H0494: 3, S0476: 2, S0474: 2, S0438: 2, H0519: 2, H0521: 2, L0754: 2, H0170: 1, S0040: 1, S0114: 1, H0484: 1, H0483: 1, H0255: 1, S0376: 1, S0444: 1, S0408: 1, S0046: 1, H0619: 1, H0549: 1, H0042: 1, H0581: 1, H0052: 1, H0083: 1, S0440: 1, L0773: 1, L0517: 1, L0383: 1, S0374: 1, S0152: 1, S3014: 1, L0751: 1, L0759: 1, S0434: 1, S0436: 1, H0543: 1 and H0422: 1. 43 HCLBK61 845659 53 AR185: 98, AR096: 71, AR055: 67, AR104: 53, AR240: 51, AR089: 49, AR219: 36, AR218: 34, AR299: 28, AR316: 27, AR300: 25, AR039: 24, AR277: 22, AR060: 21, AR313: 20, AR283: 18, AR282: 17, H0156: 3, H0052: 3, L0731: 3, T0040: 2, H0599: 2, S0010: 2, H0050: 2, H0012: 2, H0201: 2, S6028: 2, H0188: 2, H0628: 2, H0038: 2, L0796: 2, S0037: 2, S3014: 2, S0032: 2, L0777: 2, S0114: 1, S0212: 1, H0663: 1, S0418: 1, H0735: 1, H0351: 1, H0550: 1, T0039: 1, H0013: 1, H0004: 1, H0318: 1, L0738: 1, H0544: 1, H0545: 1, H0009: 1, H0123: 1, H0024: 1, H0594: 1, S0022: 1, H0031: 1, H0644: 1, H0135: 1, H0090: 1, H0616: 1, T0041: 1, H0646: 1, S0210: 1, L3905: 1, L0761: 1, L0521: 1, L0807: 1, L0809: 1, L0789: 1, S0310: 1, S0126: 1, H0658: 1, S0044: 1, S0406: 1, S0027: 1, S0028: 1, S0206: 1, L0748: 1, L0439: 1, L0740: 1, L0751: 1, L0779: 1, L0759: 1, S0436: 1, L0485: 1, L0599: 1, L0594: 1, L0603: 1, S0194: 1 and S0276: 1. 44 HCMSX51 788643 54 L0740: 16, L0745: 7, L0439: 6, L0438: 4, H0547: 4, L0750: 4, L0759: 4, H0619: 3, H0618: 3, L0770: 3, L3828: 3, L0749: 3, L0758: 3, H0393: 2, H0599: 2, H0083: 2, H0124: 2, H0623: 2, H0100: 2, L3905: 2, L0794: 2, L0809: 2, L3825: 2, L3829: 2, S0406: 2, S0027: 2, L0743: 2, L0746: 2, L0777: 2, L0603: 2, S0040: 1, L2879: 1, L2906: 1, S0420: 1, S0442: 1, S0358: 1, L3311: 1, L3485: 1, H0261: 1, H0392: 1, H0013: 1, H0250: 1, H0590: 1, H0196: 1, H0545: 1, H0046: 1, H0123: 1, H0620: 1, S0051: 1, S0250: 1, H0617: 1, S0036: 1, H0135: 1, H0634: 1, H0087: 1, H0269: 1, H0561: 1, H0509: 1, H0646: 1, S0426: 1, L0763: 1, L0769: 1, L3904: 1, L0662: 1, L0363: 1, L0767: 1, L0768: 1, L0650: 1, L0375: 1, L0806: 1, L0776: 1, L0657: 1, L0787: 1, L4559: 1, L0664: 1, L2260: 1, H0520: 1, L3831: 1, H0670: 1, H0518: 1, L3834: 1, H0704: 1, H0436: 1, L0747: 1, L0780: 1, L0608: 1, L0595: 1, and H0423: 1. 45 HCNCO11 775086 55 AR055: 2, AR060: 2, AR277: 1, AR282: 1, H0597: 1 46 HCNSD29 862314 56 AR252: 128, AR253: 67, AR245: 63, AR272: 55, AR308: 49, AR246: 47, AR263: 46, AR212: 40, AR053: 37, AR243: 35, AR312: 34, AR254: 33, AR275: 33, AR205: 33, AR309: 32, AR264: 31, AR250: 31, AR197: 31, AR271: 29, AR224: 26, AR195: 26, AR311: 26, AR200: 26, AR223: 26, AR201: 25, AR198: 25, AR219: 23, AR274: 22, AR210: 22, AR172: 21, AR218: 21, AR222: 21, AR225: 20, AR221: 20, AR268: 19, AR104: 19, AR096: 18, AR240: 17, AR188: 17, AR313: 17, AR199: 17, AR213: 17, AR203: 16, AR242: 16, AR039: 15, AR316: 15, AR170: 15, AR193: 15, AR180: 15, AR165: 14, AR269: 14, AR192: 14, AR204: 14, AR164: 14, AR166: 14, AR211: 13, AR033: 13, AR168: 13, AR270: 13, AR207: 12, AR175: 12, AR290: 12, AR169: 12, AR089: 12, AR183: 12, AR247: 12, AR176: 11, AR171: 11, AR267: 11, AR178: 11, AR162: 11, AR161: 11, AR217: 11, AR163: 10, AR174: 10, AR229: 10, AR291: 10, AR173: 10, AR189: 9, AR214: 9, AR266: 9, AR255: 9, AR181: 8, AR196: 8, AR177: 8, AR297: 8, AR289: 8, AR299: 8, AR179: 8, AR190: 8, AR191: 8, AR300: 8, AR060: 8, AR182: 8, AR238: 7, AR216: 7, AR215: 7, AR257: 7, AR261: 7, AR262: 7, AR282: 7, AR296: 7, AR185: 7, AR293: 7, AR235: 6, AR295: 6, AR283: 6, AR231: 6, AR055: 6, AR288: 6, AR285: 6, AR287: 6, AR234: 6, AR258: 6, AR237: 5, AR239: 5, AR236: 5, AR256: 5, AR277: 5, AR286: 5, AR228: 5, AR230: 4, AR294: 4, AR226: 4, AR233: 4, AR260: 4, AR232: 4, AR061: 3, AR227: 3, L0648: 2, L0768: 2, L0766: 2, L0748: 2, L0588: 2, H0125: 1, S0468: 1, H0497: 1, H0486: 1, H0744: 1, H0231: 1, H0266: 1, H0202: 1, H0641: 1, S0422: 1, L0638: 1, L0644: 1, L5572: 1, L0662: 1, L0650: 1, L0807: 1, L0657: 1, L0663: 1, L0665: 1, H0519: 1, L0759: 1, S0026: 1 and L0718: 1. 47 HCQBH72 637548 57 AR055: 2, AR060: 2, AR299: 2, AR089: 2, AR219: 1, AR185: 1, AR039: 1, AR283: 1, AR104: 1, L0520: 4, L0754: 2, H0263: 1, H0272: 1 and H0555: 1. 48 HCQCC96 845066 58 AR252: 46, AR197: 44, AR204: 38, AR195: 35, AR253: 34, AR178: 31, AR230: 31, AR254: 31, AR233: 29, AR250: 28, AR180: 28, AR198: 28, AR266: 26, AR243: 26, AR193: 24, AR239: 23, AR061: 23, AR267: 23, AR201: 23, AR227: 22, AR229: 22, AR228: 22, AR237: 21, AR162: 21, AR181: 21, AR163: 21, AR170: 21, AR161: 20, AR257: 20, AR192: 20, AR226: 20, AR176: 19, AR234: 19, AR171: 18, AR183: 18, AR245: 18, AR271: 18, AR182: 17, AR258: 17, AR270: 17, AR179: 17, AR275: 17, AR238: 16, AR231: 16, AR296: 16, AR261: 16, AR033: 16, AR174: 15, AR185: 15, AR255: 15, AR164: 15, AR262: 15, AR207: 15, AR053: 15, AR165: 15, AR272: 14, AR256: 14, AR039: 14, AR269: 14, AR242: 14, AR166: 14, AR205: 14, AR175: 14, AR246: 14, AR300: 13, AR203: 13, AR289: 12, AR236: 12, AR104: 12, AR316: 11, AR232: 11, AR293: 11, AR055: 11, AR287: 11, AR169: 11, AR260: 11, AR235: 11, AR168: 11, AR089: 11, AR173: 10, AR308: 10, AR286: 10, AR268: 10, AR291: 10, AR060: 10, AR297: 10, AR313: 10, AR288: 10, AR212: 10, AR213: 10, AR299: 10, AR177: 10, AR188: 9, AR096: 9, AR190: 9, AR191: 9, AR294: 9, AR282: 9, AR285: 9, AR283: 9, AR172: 8, AR277: 8, AR189: 8, AR247: 8, AR309: 8, AR312: 8, AR274: 8, AR240: 7, AR218: 7, AR264: 7, AR210: 6, AR200: 6, AR295: 6, AR290: 6, AR219: 6, AR215: 6, AR199: 5, AR263: 5, AR196: 5, AR223: 5, AR311: 5, AR216: 5, AR214: 4, AR224: 4, AR225: 4, AR211: 4, AR217: 4, AR221: 2, AR222: 2, S0360: 5, L0748: 5, L0766: 3, H0657: 2, L3388: 2, H0581: 2, H0596: 2, H0563: 2, S0003: 2, H0328: 2, H0670: 2, L0756: 2, S0436: 2, S0026: 2, H0170: 1, H0556: 1, H0344: 1, H0650: 1, H0656: 1, H0638: 1, S0420: 1, H0675: 1, S0007: 1, H0574: 1, H0632: 1, H0013: 1, H0036: 1, S0010: 1, H0318: 1, H0052: 1, H0251: 1, H0150: 1, H0050: 1, H0090: 1, H0038: 1, S0440: 1, H0130: 1, S0142: 1, S0422: 1, H0529: 1, L0803: 1, L0659: 1, L5623: 1, L0666: 1, S0428: 1, S0126: 1, H0689: 1, H0648: 1, H0672: 1, S0330: 1, H0539: 1, S0378: 1, H0521: 1, H0522: 1, H0478: 1, L0744: 1, L0754: 1, L0779: 1, L0752: 1, S0260: 1, H0445: 1, H0343: 1, H0595: 1, S0434: 1, H0423: 1 and S0424: 1. 49 HCUDD64 835082 59 AR282: 3, AR219: 3, H0052: 3, S3012: 2, L0754: 2, H0402: 1, H0413: 1, S0374: 1, L0438: 1, L0748: 1 and L0740: 1. 50 HCWAE64 535893 60 AR277: 7, AR282: 1, H0305: 1 51 HDPCW16 840358 61 AR089: 36, AR185: 34, AR219: 34, AR218: 27, AR104: 14, AR316: 13, AR282: 12, AR277: 10, AR240: 8, AR283: 8, AR313: 7, AR096: 6, AR039: 6, AR055: 5, AR299: 4, AR300: 4, AR060: 4, L0783: 7, H0441: 5, L0666: 4, H0617: 3, L3905: 3, L0439: 3, T0049: 2, H0341: 2, H0661: 2, L0717: 2, H0009: 2, L0471: 2, H0641: 2, L0764: 2, L0662: 2, L0659: 2, L0792: 2, L0663: 2, H0521: 2, L0748: 2, H0657: 1, H0255: 1, H0664: 1, H0402: 1, S0418: 1, S0045: 1, S0046: 1, H0749: 1, H0370: 1, H0600: 1, H0497: 1, H0333: 1, H0486: 1, L0021: 1, H0706: 1, H0544: 1, H0545: 1, H0046: 1, H0041: 1, H0178: 1, L0157: 1, H0673: 1, T0069: 1, L0351: 1, H0494: 1, H0625: 1, H0649: 1, L0502: 1, L0770: 1, L0769: 1, L5575: 1, L0645: 1, L0533: 1, L0493: 1, L0517: 1, L0518: 1, L0782: 1, L0809: 1, L0787: 1, L0789: 1, L0665: 1, L0438: 1, H0520: 1, S0126: 1, H0690: 1, H0539: 1, L0609: 1, L0612: 1, L0747: 1, L0749: 1, L0786: 1, L0779: 1, L0731: 1, L0758: 1, H0653: 1, H0667: 1 and H0352: 1. 52 HDPDI72 897277 62 AR263: 7, AR039: 6, AR089: 5, AR184: 5, AR096: 4, AR313: 4, AR299: 4, AR282: 3, AR277: 3, AR240: 3, AR060: 3, AR218: 3, AR249: 3, AR316: 3, AR185: 2, AR055: 2, AR274: 2, AR104: 2, AR267: 2, AR247: 2, AR300: 2, AR206: 1, AR283: 1, AR052: 1, AR312: 1, AR275: 1, AR183: 1, AR270: 1, AR309: 1, AR238: 1, H0521: 2 and H0580: 1. 53 HDPGE24 801947 63 H0555: 8, S0002: 7, L0748: 6, H0556: 5, H0179: 5, L0369: 5, S0222: 4, S0474: 4, S0045: 3, H0427: 3, H0599: 3, H0575: 3, H0271: 3, H0628: 3, H0598: 3, S0426: 3, L0766: 3, L0581: 3, H0265: 2, S0114: 2, S0212: 2, H0402: 2, S0442: 2, S0354: 2, S0132: 2, H0431: 2, H0370: 2, H0632: 2, H0581: 2, H0196: 2, H0050: 2, H0124: 2, L0665: 2, H0521: 2, S0390: 2, S0028: 2, L0777: 2, H0444: 2, S0436: 2, H0423: 2, L3643: 1, S0040: 1, L0002: 1, H0381: 1, S0116: 1, H0255: 1, H0662: 1, S0360: 1, H0676: 1, H0580: 1, H0729: 1, H0722: 1, H0728: 1, S0046: 1, H0749: 1, S0300: 1, L0717: 1, L3388: 1, H0586: 1, H0333: 1, H0486: 1, H0706: 1, H0036: 1, T0048: 1, H0318: 1, H0251: 1, H0309: 1, H0121: 1, H0544: 1, S0050: 1, H0375: 1, H0266: 1, S0003: 1, S0214: 1, H0252: 1, H0031: 1, H0644: 1, H0708: 1, H0400: 1, H0063: 1, H0264: 1, S0038: 1, H0280: 1, H0334: 1, H0625: 1, S0440: 1, H0509: 1, H0132: 1, S0210: 1, L0803: 1, L0525: 1, L0555: 1, L0529: 1, L0367: 1, L0532: 1, S0052: 1, S0428: 1, S0216: 1, H0547: 1, H0519: 1, S0126: 1, H0134: 1, S0406: 1, H0727: 1, H0345: 1, S0037: 1, L0740: 1, L0749: 1, S0031: 1, H0445: 1, H0707: 1, L0605: 1, L0604: 1, L0601: 1 and H0543: 1. 54 HDPIE44 899328 64 AR263: 6, AR265: 3, AR184: 3, AR183: 3, AR096: 3, AR313: 3, AR269: 3, AR039: 3, AR104: 2, AR312: 2, AR270: 2, AR268: 2, AR298: 2, AR296: 2, AR292: 2, AR060: 2, AR052: 2, AR282: 2, AR291: 2, AR198: 2, AR316: 2, AR192: 2, AR299: 2, AR286: 2, AR267: 2, AR218: 2, AR055: 2, AR295: 2, AR290: 2, AR283: 2, AR089: 2, AR289: 1, AR231: 1, AR213: 1, AR247: 1, AR284: 1, AR293: 1, AR053: 1, AR033: 1, AR238: 1, AR258: 1, AR182: 1, AR177: 1, AR277: 1, AR185: 1, AR310: 1, L3811: 7, L0439: 7, L0759: 5, L0591: 5, L0803: 4, H0547: 4, L0748: 4, L0755: 4, L0596: 4, H0171: 3, S0376: 3, S0007: 3, H0024: 3, H0355: 3, H0615: 3, H0428: 3, H0090: 3, H0623: 3, S0422: 3, L0794: 3, L0766: 3, L0659: 3, H0144: 3, H0658: 3, S0406: 3, L0749: 3, L0758: 3, S0436: 3, H0624: 2, H0717: 2, S0358: 2, S0360: 2, H0486: 2, H0427: 2, S0010: 2, H0052: 2, H0251: 2, H0687: 2, H0622: 2, H0553: 2, H0644: 2, H0591: 2, S0438: 2, L0769: 2, L0662: 2, L0805: 2, S0374: 2, S0126: 2, H0689: 2, H0670: 2, H0521: 2, S0028: 2, L0744: 2, L0740: 2, L0754: 2, L0752: 2, L0593: 2, S0192: 2, H0506: 2, H0265: 1, H0294: 1, H0656: 1, S0212: 1, L0481: 1, S0418: 1, L0005: 1, S0356: 1, S0442: 1, S0408: 1, H0733: 1, H0208: 1, S0045: 1, H0619: 1, L0717: 1, S0222: 1, H0455: 1, L3653: 1, H0013: 1, H0599: 1, S0474: 1, H0196: 1, H0263: 1, H0046: 1, H0172: 1, H0050: 1, L0471: 1, H0012: 1, H0620: 1, H0014: 1, H0051: 1, H0356: 1, H0375: 1, S0316: 1, H0328: 1, H0688: 1, L0483: 1, S0364: 1, S0366: 1, H0135: 1, H0163: 1, H0038: 1, H0040: 1, H0634: 1, H0551: 1, H0488: 1, T0042: 1, H0494: 1, S0016: 1, H0625: 1, H0561: 1, S0440: 1, L2270: 1, S0344: 1, L3818: 1, H0538: 1, L0598: 1, L0770: 1, L0638: 1, L0641: 1, L0626: 1, L0804: 1, L0375: 1, L0784: 1, L0523: 1, L0806: 1, L0776: 1, L0526: 1, L0809: 1, L5622: 1, L0789: 1, L0793: 1, L4559: 1, L0663: 1, L4560: 1, L3826: 1, L3828: 1, H0683: 1, H0672: 1, H0651: 1, S0330: 1, H0539: 1, H0555: 1, S0390: 1, S0206: 1, L0747: 1, L0779: 1, S0308: 1, L0604: 1 and H0423: 1. 55 HDPIU94 813352 65 AR055: 17, AR277: 13, AR060: 12, AR316: 9, AR219: 8, AR240: 8, AR089: 8, AR300: 8, AR218: 8, AR039: 7, AR283: 7, AR096: 6, AR282: 5, AR104: 5, AR185: 4, AR299: 4, AR313: 2, L0748: 6, L0666: 5, L0665: 5, L0768: 4, L0777: 4, L0595: 4, H0352: 4, S0045: 3, H0124: 3, L0774: 3, S0028: 3, L0439: 3, L0756: 3, L0592: 3, S0376: 2, S0360: 2, H0619: 2, S0222: 2, L3816: 2, H0635: 2, H0036: 2, H0052: 2, H0046: 2, L0041: 2, S0312: 2, H0551: 2, L3815: 2, L0764: 2, L0663: 2, H0144: 2, L3825: 2, L0751: 2, L0754: 2, L0745: 2, L0731: 2, L0589: 2, H0653: 2, H0136: 2, H0216: 2, H0624: 1, S6024: 1, S0430: 1, H0656: 1, H0255: 1, S0046: 1, H0747: 1, H0645: 1, L2759: 1, H0013: 1, H0156: 1, H0575: 1, H0050: 1, S0050: 1, H0373: 1, H0687: 1, S0314: 1, S0250: 1, H0031: 1, H0135: 1, H0634: 1, H0616: 1, H0380: 1, H0264: 1, H0433: 1, H0059: 1, L0351: 1, S0422: 1, L0800: 1, L0662: 1, L0626: 1, L0766: 1, L0803: 1, L0375: 1, L0655: 1, L0659: 1, L0783: 1, L0809: 1, L0664: 1, L2263: 1, L2258: 1, L2259: 1, H0726: 1, L3826: 1, L3827: 1, H0648: 1, S0152: 1, L3833: 1, H0521: 1, S0390: 1, S3014: 1, S0027: 1, L0749: 1, L0750: 1, L0780: 1, L0758: 1, L0759: 1, S0260: 1 and L0366: 1. 56 HDPIY31 886159 66 AR214: 26, AR263: 25, AR224: 21, AR222: 20, AR264: 20, AR223: 19, AR169: 18, AR221: 18, AR217: 18, AR171: 17, AR172: 17, AR195: 17, AR207: 16, AR170: 16, AR311: 16, AR235: 16, AR215: 16, AR225: 16, AR168: 15, AR216: 15, AR165: 14, AR197: 14, AR164: 14, AR162: 14, AR308: 13, AR089: 13, AR161: 13, AR166: 13, AR212: 13, AR192: 13, AR193: 13, AR163: 13, AR213: 12, AR033: 12, AR309: 12, AR242: 12, AR053: 11, AR245: 11, AR312: 11, AR210: 10, AR282: 10, AR253: 10, AR261: 10, AR254: 10, AR277: 10, AR198: 10, AR104: 10, AR295: 10, AR288: 9, AR240: 9, AR316: 9, AR299: 9, AR219: 9, AR196: 9, AR205: 9, AR271: 9, AR252: 9, AR285: 9, AR250: 9, AR297: 9, AR272: 8, AR060: 8, AR096: 8, AR177: 8, AR269: 8, AR274: 8, AR246: 8, AR313: 8, AR236: 8, AR211: 8, AR185: 8, AR286: 8, AR039: 7, AR291: 7, AR287: 7, AR275: 7, AR200: 7, AR300: 7, AR055: 7, AR229: 7, AR181: 7, AR283: 7, AR189: 7, AR218: 7, AR175: 7, AR174: 7, AR247: 7, AR238: 7, AR199: 6, AR289: 6, AR188: 6, AR293: 6, AR243: 6, AR191: 6, AR173: 6, AR266: 6, AR262: 6, AR204: 6, AR270: 6, AR226: 6, AR258: 6, AR201: 6, AR176: 6, AR268: 5, AR296: 5, AR257: 5, AR183: 5, AR182: 5, AR234: 5, AR231: 5, AR180: 5, AR255: 5, AR230: 5, AR178: 5, AR256: 5, AR290: 5, AR190: 5, AR239: 5, AR232: 5, AR260: 4, AR227: 4, AR203: 4, AR294: 4, AR267: 4, AR061: 4, AR179: 4, AR237: 4, AR233: 3, AR228: 3, L0439: 56, L0438: 20, H0556: 7, H0052: 7, L0776: 5, S0222: 4, H0438: 4, S0418: 3, S0278: 3, L0770: 3, L0771: 3, L0743: 3, L0366: 3, H0265: 2, S0040: 2, L0415: 2, S0045: 2, H0619: 2, H0492: 2, H0486: 2, H0581: 2, H0620: 2, H0266: 2, H0604: 2, H0031: 2, H0100: 2, L0351: 2, H0144: 2, L0352: 2, H0672: 2, H0521: 2, L0756: 2, L0777: 2, L0731: 2, H0624: 1, H0140: 1, H0583: 1, H0255: 1, H0402: 1, H0305: 1, H0458: 1, S0420: 1, S0354: 1, S0358: 1, H0645: 1, S6022: 1, H0392: 1, H0643: 1, H0559: 1, H0013: 1, H0069: 1, H0156: 1, H0590: 1, S0346: 1, H0085: 1, H0544: 1, H0545: 1, H0439: 1, H0150: 1, H0041: 1, S0388: 1, S0051: 1, T0010: 1, H0271: 1, H0416: 1, H0188: 1, H0288: 1, S0022: 1, T0006: 1, H0213: 1, H0628: 1, H0617: 1, H0135: 1, H0087: 1, H0551: 1, H0477: 1, H0059: 1, S0038: 1, L0435: 1, T0042: 1, H0494: 1, S0344: 1, S0426: 1, L0640: 1, L0769: 1, L0638: 1, L0761: 1, L0642: 1, L0764: 1, L0768: 1, L0794: 1, L0803: 1, L0375: 1, L0806: 1, L0805: 1, L0655: 1, L0659: 1, L0809: 1, L0789: 1, L0665: 1, H0519: 1, S0126: 1, H0690: 1, H0682: 1, S0330: 1, H0539: 1, H0522: 1, S0037: 1, L0751: 1, L0754: 1, L0746: 1, L0749: 1, L0786: 1, L0779: 1, H0445: 1, L0596: 1, H0542: 1 and H0543: 1. 57 HDPOC24 777493 67 H0585: 26, H0141: 12, L0666: 9, L0754: 9, L0755: 9, S0212: 6, L0663: 5, L0743: 5, S0356: 4, H0587: 4, H0553: 4, L0657: 4, L0382: 4, L0740: 4, L0747: 4, S0045: 3, S0046: 3, H0024: 3, L0771: 3, L0648: 3, L0662: 3, L0659: 3, L0664: 3, S0126: 3, H0522: 3, L0748: 3, L0777: 3, L0757: 3, S0192: 3, S0040: 2, S0420: 2, S0442: 2, S0358: 2, S0476: 2, H0550: 2, H0497: 2, H0250: 2, H0575: 2, H0052: 2, H0546: 2, H0266: 2, H0100: 2, H0646: 2, S0002: 2, L0763: 2, L0649: 2, L0803: 2, L0775: 2, L0653: 2, L0517: 2, L0809: 2, L0790: 2, L0665: 2, H0660: 2, S0380: 2, H0521: 2, S3014: 2, S0028: 2, L0751: 2, S0436: 2, H0665: 2, S0430: 1, H0341: 1, S0282: 1, H0664: 1, S0418: 1, S0354: 1, S0444: 1, H0549: 1, S0222: 1, H0600: 1, H0333: 1, H0618: 1, H0253: 1, S0474: 1, H0581: 1, H0235: 1, H0597: 1, H0545: 1, H0009: 1, H0081: 1, H0620: 1, H0023: 1, H0687: 1, S0250: 1, L0483: 1, T0006: 1, L0055: 1, H0087: 1, H0551: 1, H0379: 1, H0264: 1, H0494: 1, H0625: 1, S0352: 1, H0641: 1, H0529: 1, L0371: 1, L0769: 1, L5575: 1, L3905: 1, L5566: 1, L0772: 1, L0800: 1, L0764: 1, L0773: 1, L0794: 1, L0386: 1, L0378: 1, L0806: 1, L0807: 1, L0792: 1, L0565: 1, S0310: 1, H0519: 1, H0682: 1, H0684: 1, H0670: 1, H0672: 1, S0328: 1, S0330: 1, S0332: 1, H0478: 1, S0432: 1, S3012: 1, S0390: 1, S0206: 1, L0742: 1, L0756: 1, L0779: 1, H0707: 1, S0434: 1, L0596: 1, H0668: 1, S0242: 1, H0506: 1 and H0008: 1. 58 HDPPD93 637588 68 AR202: 68, AR194: 68, AR281: 64, AR244: 59, AR315: 56, AR205: 52, AR246: 50, AR280: 49, AR283: 45, AR314: 39, AR271: 38, AR232: 37, AR243: 37, AR241: 35, AR316: 34, AR282: 33, AR204: 33, AR263: 32, AR089: 32, AR192: 32, AR265: 31, AR277: 31, AR206: 30, AR219: 29, AR310: 29, AR033: 29, AR096: 29, AR313: 28, AR299: 28, AR240: 26, AR247: 26, AR273: 24, AR300: 24, AR198: 24, AR295: 24, AR274: 24, AR218: 24, AR039: 23, AR275: 23, AR055: 23, AR213: 23, AR104: 22, AR251: 22, AR238: 20, AR177: 20, AR312: 20, AR060: 19, AR226: 19, AR052: 19, AR231: 18, AR053: 18, AR309: 18, AR234: 18, AR227: 18, AR185: 17, AR292: 17, AR237: 17, AR229: 16, AR258: 16, AR183: 16, AR175: 15, AR294: 14, AR256: 13, AR259: 13, AR233: 13, AR293: 11, AR186: 11, AR253: 10, AR061: 10, AR266: 10, AR267: 9, AR285: 8, AR248: 8, AR270: 8, AR296: 8, AR284: 7, AR179: 7, AR289: 7, AR249: 7, AR268: 6, AR269: 6, AR291: 6, AR184: 6, AR298: 5, AR286: 5, AR182: 5, AR290: 4, L0794: 6, L0748: 6, H0556: 5, L0771: 5, H0052: 4, L0756: 4, L0596: 4, H0265: 3, H0341: 3, H0587: 3, L0662: 3, L0803: 3, L0790: 3, S0152: 3, L0750: 3, S0114: 2, S0360: 2, H0318: 2, L0471: 2, L0369: 2, L0763: 2, L0770: 2, L0764: 2, L0766: 2, L0774: 2, L0378: 2, L0789: 2, L0666: 2, L3825: 2, H0547: 2, L0747: 2, L0777: 2, L0581: 2, H0543: 2, H0422: 2, S0218: 1, H0255: 1, S0418: 1, S0354: 1, S0376: 1, S0408: 1, L3649: 1, S0045: 1, H0747: 1, H0619: 1, L0717: 1, S0222: 1, H0431: 1, H0586: 1, H0013: 1, H0069: 1, S0049: 1, H0009: 1, H0071: 1, H0083: 1, H0428: 1, T0006: 1, H0424: 1, H0213: 1, H0644: 1, H0628: 1, H0135: 1, H0163: 1, H0616: 1, H0413: 1, H0059: 1, H0561: 1, S0448: 1, H0647: 1, L3818: 1, S0002: 1, L0769: 1, L0800: 1, L0363: 1, L0767: 1, L0768: 1, L0649: 1, L0804: 1, L0806: 1, L0657: 1, L0512: 1, L0659: 1, L0384: 1, L0647: 1, L5622: 1, L5623: 1, L0664: 1, L0665: 1, S0374: 1, L3828: 1, S0126: 1, H0711: 1, H0658: 1, H0666: 1, H0539: 1, H0753: 1, H0521: 1, H0522: 1, S0406: 1, H0555: 1, H0436: 1, L0439: 1, L0749: 1, S0031: 1, L0595: 1, H0136: 1, H0542: 1, H0423: 1, S0424: 1 and H0352: 1. 59 HDPPQ30 684292 69 H0542: 4, S0250: 3, H0521: 3, H0522: 3, H0485: 2, H0486: 1, H0494: 1 and H0543: 1. 60 HDQHM36 852328 70 AR313: 50, AR039: 48, AR277: 28, AR089: 26, AR096: 26, AR300: 25, AR185: 23, AR299: 22, AR240: 17, AR316: 17, AR104: 15, AR219: 12, AR282: 12, AR218: 12, AR060: 10, AR055: 6, AR283: 5, H0521: 2 61 HDTLM18 836057 71 AR313: 9, AR089: 5, AR299: 5, AR185: 4, AR300: 3, AR060: 3, AR096: 3, AR282: 3, AR039: 2, AR316: 2, AR055: 2, AR104: 2, AR240: 1, AR277: 1, AR283: 1, H0486: 1 and L0599: 1. 62 HE2CM39 553651 72 AR277: 46, AR283: 32, AR219: 30, AR313: 29, AR218: 25, AR316: 25, AR089: 24, AR299: 23, AR104: 23, AR282: 23, AR055: 21, AR300: 20, AR185: 18, AR039: 18, AR096: 17, AR240: 17, AR060: 13, L0759: 4, L0657: 3, L0789: 3, L0439: 3, L0752: 3, L0758: 3, S0360: 2, L0805: 2, L0438: 2, L0750: 2, L0777: 2, H0423: 2, H0171: 1, H0638: 1, H0351: 1, H0178: 1, H0606: 1, L0625: 1, L0769: 1, L0771: 1, L0662: 1, L0794: 1, L0803: 1, L0804: 1, L0650: 1, L0774: 1, L0659: 1, L0809: 1, L0663: 1, H0436: 1, L0748: 1, L0740: 1, H0445: 1, L0604: 1 and H0422: 1. 63 HE6CS65 762960 73 AR219: 61, AR277: 59, AR218: 48, AR283: 47, AR282: 43, AR316: 39, AR089: 38, AR313: 36, AR299: 34, AR240: 33, AR104: 29, AR055: 29, AR096: 29, AR039: 27, AR185: 26, AR300: 22, AR060: 21, L0777: 16, L0748: 12, L0757: 11, L0776: 8, L0439: 7, H0692: 6, H0046: 6, L0769: 5, L0666: 5, S0242: 5, L0770: 4, L0771: 4, L0438: 4, L0743: 4, L0754: 4, L0749: 4, L0758: 4, S0444: 3, H0051: 3, L0662: 3, L0766: 3, S0378: 3, L0751: 3, L0747: 3, S0436: 3, S0212: 2, H0637: 2, H0497: 2, H0545: 2, H0050: 2, H0031: 2, H0090: 2, H0100: 2, L0768: 2, L0561: 2, L0774: 2, L0775: 2, L0657: 2, H0670: 2, S3014: 2, L0744: 2, L0752: 2, L0581: 2, H0624: 1, H0170: 1, H0713: 1, H0717: 1, S6024: 1, T0049: 1, H0255: 1, S0356: 1, S0442: 1, S0358: 1, S0376: 1, S0360: 1, H0619: 1, L3651: 1, L0717: 1, S0278: 1, H0391: 1, H0333: 1, H0013: 1, H0053: 1, H0575: 1, S0346: 1, H0052: 1, H0263: 1, H0596: 1, L0738: 1, H0572: 1, H0510: 1, H0266: 1, H0688: 1, H0039: 1, H0622: 1, H0111: 1, H0181: 1, H0617: 1, H0032: 1, H0169: 1, H0634: 1, H0087: 1, H0412: 1, S0450: 1, S0440: 1, L0639: 1, L0637: 1, L0372: 1, L0646: 1, L0651: 1, L0806: 1, L0659: 1, L0792: 1, L0664: 1, L0665: 1, S0216: 1, H0144: 1, H0697: 1, S0374: 1, L3812: 1, H0520: 1, H0547: 1, H0658: 1, H0660: 1, H0648: 1, H0521: 1, H0696: 1, S0027: 1, S0028: 1, L0741: 1, L0740: 1, L0779: 1, L0731: 1, L0759: 1, S0260: 1, H0445: 1, S0434: 1, L0362: 1 and L0366: 1. 64 HE6FU11 827236 74 AR089: 8, AR104: 6, AR039: 6, AR096: 5, AR060: 5, AR313: 5, AR185: 5, AR055: 4, AR284: 4, AR266: 4, AR316: 4, AR282: 4, AR292: 4, AR299: 4, AR202: 4, AR218: 3, AR289: 3, AR283: 3, AR298: 3, AR277: 3, AR182: 3, AR184: 3, AR280: 3, AR250: 3, AR219: 3, AR315: 3, AR281: 3, AR300: 3, AR169: 3, AR294: 3, AR240: 3, AR291: 3, AR268: 2, AR172: 2, AR033: 2, AR270: 2, AR248: 2, AR310: 2, AR175: 2, AR238: 2, AR241: 2, AR265: 2, AR232: 2, AR285: 2, AR183: 2, AR177: 2, AR227: 2, AR269: 2, AR263: 2, AR290: 2, AR288: 2, AR293: 2, AR229: 2, AR267: 2, AR061: 2, AR176: 2, AR257: 2, AR271: 2, AR296: 2, AR286: 2, AR272: 2, AR259: 1, AR206: 1, AR256: 1, AR214: 1, AR231: 1, AR247: 1, AR295: 1, AR204: 1, AR237: 1, AR226: 1, AR234: 1, AR308: 1, AR253: 1, AR053: 1, AR311: 1, AR205: 1, AR243: 1, AR233: 1, AR173: 1, AR312: 1, AR251: 1, AR314: 1, L0759: 2, H0706: 1, H0123: 1, H0024: 1, H0100: 1, L0794: 1 and L0789: 1. 65 HE6FV29 588454 75 AR219: 37, AR218: 36, AR315: 34, AR280: 34, AR271: 33, AR244: 29, AR089: 29, AR314: 29, AR243: 28, AR281: 26, AR282: 25, AR273: 25, AR205: 24, AR192: 22, AR206: 22, AR198: 19, AR247: 19, AR316: 19, AR039: 19, AR231: 18, AR269: 17, AR246: 17, AR204: 16, AR234: 16, AR299: 16, AR313: 15, AR194: 15, AR055: 14, AR186: 14, AR237: 14, AR060: 14, AR241: 13, AR270: 13, AR293: 12, AR240: 12, AR232: 11, AR238: 11, AR251: 10, AR300: 10, AR061: 10, AR233: 10, AR227: 10, AR291: 9, AR185: 9, AR202: 9, AR266: 9, AR226: 9, AR229: 9, AR184: 8, AR179: 8, AR182: 8, AR175: 8, AR312: 8, AR268: 8, AR289: 7, AR284: 7, AR249: 7, AR183: 7, AR310: 7, AR267: 7, AR052: 7, AR033: 7, AR296: 7, AR290: 7, AR265: 7, AR177: 7, AR309: 7, AR292: 6, AR298: 6, AR275: 6, AR277: 6, AR285: 6, AR294: 5, AR248: 5, AR053: 5, AR253: 5, AR295: 5, AR286: 5, AR259: 5, AR274: 4, AR258: 4, AR213: 4, AR096: 4, AR256: 4, AR104: 4, AR283: 3, AR263: 2, S0440: 32, S0476: 22, H0494: 20, L0754: 17, S0372: 16, S0132: 13, L0666: 13, S0330: 13, H0046: 12, H0586: 11, H0587: 11, S0328: 11, S0360: 10, S0436: 9, S0356: 8, H0622: 8, S0003: 7, L0806: 7, H0648: 7, L0747: 7, L0752: 7, H0674: 6, L0777: 6, L0362: 6, L0662: 5, L0659: 5, L0601: 5, S0430: 4, S0358: 4, S0408: 4, H0592: 4, S0214: 4, H0039: 4, H0031: 4, H0551: 4, H0264: 4, H0560: 4, L0763: 4, L0653: 4, L5623: 4, L0663: 4, S0376: 3, S0444: 3, S0410: 3, H0370: 3, H0600: 3, H0644: 3, L0646: 3, L0649: 3, L0776: 3, L0783: 3, L0809: 3, L0665: 3, H0696: 3, S0406: 3, S3014: 3, L0755: 3, S0434: 3, L0591: 3, H0170: 2, S0134: 2, H0662: 2, S0442: 2, H0393: 2, H0596: 2, H0597: 2, H0688: 2, H0553: 2, H0032: 2, H0169: 2, H0598: 2, H0090: 2, H0379: 2, H0380: 2, L0770: 2, L0372: 2, L0549: 2, L0376: 2, L0517: 2, L0518: 2, L5622: 2, H0658: 2, H0670: 2, S0380: 2, S0152: 2, S0350: 2, S0027: 2, L0744: 2, L0779: 2, L0759: 2, L0599: 2, S0196: 2, S0456: 2, H0171: 1, H0556: 1, T0002: 1, H0713: 1, H0483: 1, H0663: 1, L0005: 1, S0354: 1, T0008: 1, H0742: 1, H0741: 1, H0411: 1, H0549: 1, T0039: 1, H0013: 1, L0021: 1, H0349: 1, S0010: 1, H0204: 1, L0738: 1, H0545: 1, H0014: 1, H0015: 1, H0373: 1, H0355: 1, H0510: 1, H0615: 1, L0483: 1, L0142: 1, L0143: 1, H0166: 1, H0673: 1, H0708: 1, H0591: 1, H0038: 1, H0040: 1, H0634: 1, T0067: 1, H0272: 1, H0487: 1, H0412: 1, H0623: 1, H0059: 1, H0100: 1, S0352: 1, S0382: 1, S0448: 1, S0306: 1, S0438: 1, S0472: 1, H0646: 1, L0503: 1, L0640: 1, L0637: 1, L0761: 1, L0772: 1, L0764: 1, L0771: 1, L0648: 1, L0794: 1, L5564: 1, L0551: 1, L0805: 1, L0382: 1, L0519: 1, L0789: 1, L0532: 1, L0664: 1, H0144: 1, H0520: 1, H0547: 1, S0126: 1, H0689: 1, H0711: 1, H0435: 1, H0659: 1, H0666: 1, S0378: 1, H0704: 1, S0044: 1, H0555: 1, S0392: 1, S0322: 1, L0748: 1, L0740: 1, L0745: 1, L0749: 1, L0756: 1, L0757: 1 and S0242: 1. 66 HE8BQ49 589443 76 H0013: 2 67 HE8SG96 862016 77 AR052: 43, AR184: 40, AR248: 40, AR249: 35, AR253: 33, AR312: 30, AR053: 28, AR313: 25, AR265: 24, AR213: 24, AR310: 23, AR096: 22, AR173: 22, AR263: 21, AR165: 20, AR309: 20, AR164: 19, AR247: 18, AR183: 18, AR166: 18, AR257: 17, AR299: 17, AR290: 17, AR269: 17, AR270: 17, AR175: 17, AR218: 16, AR268: 16, AR258: 16, AR238: 15, AR229: 15, AR292: 15, AR162: 15, AR161: 15, AR293: 14, AR300: 14, AR262: 14, AR163: 14, AR284: 14, AR259: 13, A2R251: 13, AR219: 13, AR039: 13, AR226: 13, AR267: 12, AR296: 12, AR182: 12, AR231: 12, AR240: 11, AR177: 11, AR285: 11, AR298: 11, AR179: 11, AR191: 11, AR237: 10, AR281: 10, AR236: 10, AR291: 10, AR286: 10, AR316: 10, AR260: 10, AR089: 10, AR294: 10, AR228: 9, AR234: 9, AR255: 9, AR280: 9, AR315: 9, AR199: 9, AR282: 8, AR239: 8, AR314: 8, AR185: 8, AR256: 8, AR196: 8, AR033: 8, AR295: 8, AR289: 8, AR055: 8, AR287: 7, AR235: 7, AR288: 7, AR212: 7, AR232: 7, AR266: 7, AR203: 7, AR180: 7, AR178: 6, AR242: 6, AR061: 6, AR261: 6, AR297: 6, AR200: 6, AR277: 6, AR197: 6, AR230: 6, AR189: 6, AR233: 6, AR250: 6, AR227: 6, AR264: 6, AR192: 5, AR207: 5, AR172: 5, AR308: 5, AR245: 5, AR193: 5, AR181: 5, AR060: 5, AR170: 5, AR168: 5, AR188: 5, AR171: 4, AR311: 4, AR214: 4, AR283: 4, AR216: 4, AR241: 4, AR210: 4, AR223: 4, AR190: 4, AR104: 4, AR195: 4, AR201: 4, AR224: 4, AR254: 3, AR222: 3, AR275: 3, AR217: 3, AR274: 3, AR169: 3, AR225: 3, AR272: 3, AR211: 3, AR204: 3, AR186: 2, AR271: 2, AR205: 2, AR198: 2, AR176: 2, AR243: 2, AR174: 2, AR215: 1, H0244: 1 and S0106: 1. 68 HE9EA10 827796 78 L0794: 12, H0620: 3, L0756: 2, L0759: 2, S0408: 1, S0049: 1, H0544: 1, H0012: 1, H0615: 1, H0040: 1, L0764: 1, L0803: 1, L0806: 1, L0789: 1, H0144: 1, H0547: 1, L0779: 1, L0597: 1 and L0595: 1. 69 HE9GG20 633719 79 AR104: 15, AR055: 10, AR089: 10, AR060: 9, AR277: 7, AR185: 7, AR300: 7, AR218: 6, AR299: 6, AR313: 6, AR096: 6, AR282: 5, AR316: 5, AR219: 5, AR283: 5, AR039: 5, AR240: 5, L0748: 6, H0144: 3, S0010: 2, S0474: 2, L0439: 2, L0749: 2, H0717: 1, H0662: 1, H0734: 1, S6022: 1, S0222: 1, S0280: 1, L0109: 1, H0163: 1, L0639: 1, L0659: 1, L0744: 1, L0745: 1, L0747: 1, L0756: 1, L0596: 1 and S0276: 1. 70 HEAAW94 847340 80 AR282: 3, AR218: 3, AR299: 2, AR039: 2, AR277: 2, AR096: 1, AR316: 1, AR055: 1, AR300: 1, L0439: 26, L0438: 20, L0748: 17, L0766: 16, L0754: 16, L0731: 16, H0556: 9, L0740: 8, S0222: 7, H0090: 7, L0774: 7, H0144: 6, L0745: 6, L0779: 6, L0777: 6, L0758: 6, S0003: 5, L0662: 5, L0794: 5, S0418: 4, H0575: 4, L0776: 4, L0751: 4, L0749: 4, L0756: 4, L0780: 4, L0752: 4, L0591: 4, H0423: 4, H0341: 3, S0360: 3, H0369: 3, H0156: 3, L0435: 3, L0769: 3, L0775: 3, L0809: 3, L0666: 3, H0547: 3, S0328: 3, H0521: 3, L0747: 3, L0750: 3, H0543: 3, H0171: 2, S0442: 2, S0354: 2, S0358: 2, S0132: 2, S0278: 2, H0497: 2, T0039: 2, H0706: 2, H0036: 2, S0474: 2, H0596: 2, H0009: 2, H0375: 2, S6028: 2, H0266: 2, S0214: 2, H0328: 2, H0622: 2, H0644: 2, H0591: 2, H0413: 2, T0041: 2, L0770: 2, L0796: 2, L0363: 2, L0806: 2, L0659: 2, L0542: 2, L0783: 2, L0791: 2, L0665: 2, L3811: 2, H0518: 2, S3014: 2, S0028: 2, H0595: 2, S0434: 2, S0436: 2, L0589: 2, L0604: 2, L0601: 2, H0542: 2, S0424: 2, L0411: 1, H0624: 1, H0170: 1, L0615: 1, H0265: 1, S0342: 1, S6024: 1, S0134: 1, H0657: 1, S0212: 1, H0450: 1, S0420: 1, L0005: 1, S0444: 1, H0580: 1, H0741: 1, S0045: 1, S0476: 1, H0393: 1, H0550: 1, H0441: 1, H0370: 1, H0600: 1, H0586: 1, H0587: 1, H0486: 1, H0250: 1, H0635: 1, L0021: 1, S0182: 1, L0563: 1, H0052: 1, H0309: 1, H0046: 1, L0157: 1, H0566: 1, H0081: 1, H0050: 1, H0057: 1, S0051: 1, S0318: 1, S0316: 1, H0687: 1, S0250: 1, H0615: 1, H0428: 1, H0039: 1, L0483: 1, H0553: 1, L0055: 1, H0032: 1, H0673: 1, S0366: 1, H0038: 1, H0634: 1, H0380: 1, H0488: 1, H0623: 1, H0059: 1, S0112: 1, L0351: 1, H0641: 1, H0646: 1, S0344: 1, S0002: 1, S0426: 1, L0638: 1, L4747: 1, L0761: 1, L0627: 1, L0372: 1, L0646: 1, L0374: 1, L0644: 1, L0771: 1, L0767: 1, L0768: 1, L0549: 1, L0550: 1, L0533: 1, L0804: 1, L0650: 1, L0375: 1, L0651: 1, L0523: 1, L0655: 1, L0782: 1, L0790: 1, L0663: 1, L0664: 1, S0148: 1, L0352: 1, H0520: 1, H0519: 1, S0126: 1, H0672: 1, H0754: 1, S0152: 1, H0522: 1, H0696: 1, S0044: 1, S0406: 1, L0612: 1, S3012: 1, L0746: 1, L0786: 1, L0759: 1, H0445: 1, L0684: 1, L0608: 1, H0667: 1, S0276: 1 and H0422: 1. 71 HEBCI18 831464 81 AR055: 8, AR060: 7, AR240: 7, AR185: 6, AR104: 6, AR283: 5, AR089: 5, AR300: 5, AR218: 4, AR299: 4, AR313: 4, AR316: 4, AR096: 3, AR277: 3, AR219: 2, AR039: 2, AR282: 2 72 HEBCY54 600355 82 AR104: 9, AR277: 6, AR283: 5, AR055: 4, AR096: 4, AR060: 4, AR240: 4, AR282: 2, AR316: 2, AR185: 2, AR300: 2, AR299: 2, AR089: 2, AR039: 2, AR313: 1, AR218: 1, L0438: 3, L0748: 3, T0010: 2, L0351: 2, L0769: 2, H0521: 2, L0439: 2, L0747: 2, S0116: 1, S0354: 1, S0007: 1, H0619: 1, H0253: 1, H0565: 1, H0135: 1, L0641: 1, L0521: 1, L0774: 1, L0809: 1, L0789: 1, H0520: 1, L0755: 1, L0758: 1 and H0445: 1. 73 HEBDQ91 840288 83 AR218: 18, AR219: 15, AR104: 14, AR185: 11, AR055: 10, AR060: 9, AR313: 9, AR299: 8, AR096: 7, AR089: 7, AR282: 7, AR316: 6, AR240: 6, AR277: 6, AR283: 6, AR039: 5, AR300: 5, S0007: 5, L0805: 3, S6026: 1, L0769: 1, L0438: 1, L0741: 1, L0748: 1 and L0758: 1. 74 HEBFR46 847064 84 AR313: 58, AR039: 47, AR300: 30, AR096: 29, AR299: 29, AR277: 28, AR089: 27, AR185: 27, AR316: 22, AR219: 22, AR104: 21, AR218: 20, AR240: 20, AR282: 15, AR060: 15, AR055: 11, AR283: 7, H0457: 10, H0550: 5, H0436: 5, H0549: 4, H0616: 4, L0519: 4, H0556: 3, H0580: 3, S0007: 3, S0046: 3, L0809: 3, L0747: 3, L0777: 3, S0436: 3, H0295: 2, T0040: 2, H0266: 2, L0761: 2, L0783: 2, L0789: 2, H0658: 2, H0521: 2, L0753: 2, L0731: 2, L0596: 2, H0543: 2, S0040: 1, S0116: 1, S0282: 1, H0662: 1, H0402: 1, H0125: 1, L0534: 1, L0562: 1, S0356: 1, S0358: 1, H0749: 1, L3816: 1, H0559: 1, H0069: 1, H0599: 1, H0618: 1, H0253: 1, H0581: 1, H0546: 1, H0123: 1, S0051: 1, H0083: 1, H0687: 1, H0284: 1, H0124: 1, H0038: 1, H0551: 1, H0623: 1, S0038: 1, T0041: 1, S0440: 1, S0150: 1, L3818: 1, S0002: 1, L0763: 1, L0769: 1, L5575: 1, L0627: 1, L0800: 1, L0662: 1, L0803: 1, L0793: 1, L0666: 1, L2264: 1, L3825: 1, L3827: 1, L3828: 1, H0547: 1, H0519: 1, H0539: 1, S0037: 1, S0206: 1, L0748: 1, L0749: 1, H0595: 1, L0593: 1, S0194: 1 and S0276: 1. 75 HEBGE07 798096 85 S0007: 1 76 HEBGE23 836129 86 AR282: 4, AR313: 4, AR316: 3, AR089: 3, AR060: 3, AR055: 3, AR185: 3, AR104: 2, AR240: 2, AR218: 2, AR219: 2, AR096: 2, AR299: 2, AR039: 2, AR277: 1, L0809: 7, L0758: 7, S0007: 4, L0662: 4, L0794: 4, L0665: 4, L0439: 4, L0754: 4, H0333: 3, L0769: 3, L0761: 3, L0803: 3, H0395: 2, S0222: 2, H0052: 2, H0124: 2, S0036: 2, L0535: 2, L0666: 2, H0658: 2, L0751: 2, L0747: 2, L0592: 2, L0485: 2, H0716: 1, H0295: 1, H0402: 1, H0125: 1, S0418: 1, S0442: 1, H0733: 1, H0734: 1, H0619: 1, H0586: 1, L0623: 1, H0486: 1, S0280: 1, L0021: 1, H0618: 1, H0318: 1, S0474: 1, H0251: 1, H0123: 1, H0050: 1, S0051: 1, H0179: 1, H0615: 1, T0006: 1, H0673: 1, H0087: 1, H0264: 1, H0100: 1, L0763: 1, L5565: 1, L0667: 1, L0772: 1, L0644: 1, L0768: 1, L0775: 1, L0805: 1, L0655: 1, L0659: 1, L0526: 1, L5623: 1, L0663: 1, S0052: 1, H0682: 1, H0660: 1, L0602: 1, L0743: 1, L0750: 1, L0756: 1, L0779: 1, L0777: 1, H0136: 1 and S0424: 1. 77 HEGAU15 834379 87 AR299: 9, AR039: 8, AR300: 8, AR055: 7, AR240: 7, AR060: 7, AR313: 6, AR282: 6, AR277: 6, AR104: 5, AR089: 5, AR096: 5, AR185: 5, AR316: 4, AR283: 4, AR218: 4, AR219: 3, H0550: 2, L0749: 2, H0318: 1 and H0555: 1. 78 HFCEI04 692438 88 AR055: 7, AR060: 7, AR104: 6, AR240: 6, AR282: 6, AR218: 5, AR185: 5, AR283: 5, AR089: 4, AR300: 4, AR313: 3, AR299: 3, AR316: 3, AR096: 3, AR039: 3, AR277: 3, AR219: 2, H0009: 3 79 HFEAY59 658685 89 AR055: 5, AR277: 5, AR283: 5, AR060: 4, AR282: 4, AR104: 4, AR300: 3, AR240: 3, AR316: 2, AR039: 2, AR089: 2, AR096: 2, AR218: 2, AR185: 2, AR219: 1, AR299: 1, H0081: 2 and H0586: 1. 80 HFEBO17 852218 90 AR089: 12, AR218: 11, AR060: 10, AR299: 10, AR219: 10, AR313: 9, AR055: 9, AR316: 9, AR240: 8, AR282: 8, AR096: 8, AR185: 8, AR104: 7, AR039: 7, AR277: 7, AR300: 6, AR283: 4, L0803: 4, L0438: 4, L0766: 2, L0526: 2, H0659: 2, S0444: 1, S0408: 1, H0421: 1, H0081: 1, H0050: 1, S0370: 1, L0770: 1, L0637: 1, L0646: 1, L0800: 1, L0662: 1, L0804: 1, L0607: 1, L0659: 1, L0790: 1, L0665: 1, L0352: 1, H0648: 1, H0651: 1, S0328: 1, H0436: 1, L0749: 1, L0750: 1, L0777: 1, L0752: 1, L0599: 1, S0242: 1 and H0422: 1. 81 HFIJA68 847074 91 AR241: 47, AR313: 34, AR039: 26, AR089: 24, AR198: 24, AR192: 23, AR204: 18, AR183: 17, AR299: 16, AR229: 16, AR218: 16, AR096: 15, AR185: 15, AR300: 14, AR271: 14, AR275: 14, AR240: 13, AR247: 13, AR243: 12, AR238: 12, AR194: 12, AR316: 12, AR258: 12, AR226: 12, AR219: 11, AR177: 11, AR293: 11, AR274: 10, AR175: 10, AR273: 10, AR277: 10, AR233: 9, AR312: 9, AR280: 9, AR234: 9, AR104: 9, AR315: 9, AR292: 8, AR269: 8, AR231: 8, AR205: 8, AR314: 7, AR060: 7, AR295: 7, AR265: 7, AR237: 7, AR053: 7, AR179: 7, AR186: 7, AR270: 7, AR281: 7, AR052: 7, AR267: 6, AR268: 6, AR227: 6, AR294: 6, AR249: 6, AR202: 6, AR033: 6, AR182: 6, AR184: 6, AR246: 6, AR259: 6, AR256: 5, AR213: 5, AR282: 5, AR232: 4, AR206: 4, AR309: 4, AR253: 4, AR310: 4, AR296: 4, AR251: 4, AR055: 3, AR290: 3, AR248: 3, AR291: 3, AR286: 3, AR285: 2, AR298: 2, AR263: 2, AR289: 2, AR061: 2, AR244: 2, AR284: 2, AR283: 2, AR266: 1, S0194: 1 82 HFKES05 827572 92 L0777: 7, S0358: 5, L0439: 5, L0751: 5, H0135: 4, H0265: 3, H0556: 3, L0770: 3, L0769: 3, L0662: 3, L0768: 3, L0731: 3, H0305: 2, H0083: 2, L0142: 2, S0208: 2, S0002: 2, L0663: 2, L0665: 2, H0521: 2, L0741: 2, L0747: 2, L0779: 2, H0543: 2, H0149: 1, H0657: 1, S0116: 1, S0001: 1, H0663: 1, S0356: 1, S0354: 1, H0580: 1, S0045: 1, H0549: 1, S6014: 1, H0309: 1, H0085: 1, H0234: 1, H0597: 1, H0544: 1, H0546: 1, H0123: 1, H0012: 1, H0024: 1, H0356: 1, H05941, T0006: 1, H0424: 1, H0644: 1, H0182: 1, H0617: 1, L0055: 1, H0673: 1, H0169: 1, H0038: 1, H0040: 1, H0100: 1, L0351: 1, T0041: 1, H0561: 1, H0132: 1, L0763: 1, L0638: 1, L0637: 1, L0372: 1, L0765: 1, L0648: 1, L0649: 1, L0774: 1, L0375: 1, L0807: 1, L0545: 1, L0529: 1, L0788: 1, L0666: 1, L0664: 1, S0374: 1, H0691: 1, H0658: 1, H0670: 1, H0666: 1, S0044: 1, S0028: 1, L0744: 1, L0749: 1, L0755: 1, L0758: 1, H0445: 1, S0436: 1, L0593: 1 and H0352: 1. 83 HFKFX64 566835 93 AR273: 15, AR244: 9, AR274: 9, AR192: 9, AR184: 8, AR186: 8, AR204: 8, AR052: 7, AR243: 7, AR202: 7, AR269: 7, AR271: 6, AR198: 6, AR206: 6, AR312: 6, AR246: 6, AR247: 6, AR241: 5, AR213: 5, AR275: 5, AR309: 5, AR253: 5, AR061: 5, AR055: 5, AR267: 5, AR182: 5, AR060: 5, AR268: 4, AR053: 4, AR282: 4, AR205: 4, AR194: 4, AR185: 4, AR033: 3, AR183: 3, AR277: 3, AR270: 3, AR240: 3, AR266: 3, AR310: 3, AR104: 3, AR291: 3, AR313: 3, AR248: 3, AR219: 3, AR249: 3, AR265: 3, AR251: 3, AR300: 3, AR295: 2, AR229: 2, AR237: 2, AR294: 2, AR299: 2, AR218: 2, AR293: 2, AR233: 2, AR238: 2, AR283: 2, AR292: 2, AR175: 2, AR226: 2, AR316: 2, AR039: 2, AR089: 2, AR227: 2, AR296: 2, AR231: 2, AR234: 2, AR289: 2, AR096: 2, AR298: 2, AR177: 2, AR286: 1, AR259: 1, AR256: 1, AR179: 1, AR263: 1, H0012: 3 and L0809: 1. 84 HFPCZ55 840840 94 L0756: 6, L0439: 4, L0777: 4, L0662: 3, H0672: 3, S0358: 2, L0659: 2, L0666: 2, S0031: 2, S0360: 1, H0411: 1, H0369: 1, S0222: 1, S0220: 1, S0005: 1, H0575: 1, T0082: 1, H0050: 1, S6028: 1, H0169: 1, H0100: 1, L0769: 1, L0774: 1, L0776: 1, L0647: 1, L0663: 1, H0660: 1, H0651: 1, S0146: 1, L0743: 1, L0757: 1, L0361: 1 and L0462: 1. 85 HFTAS49 847386 95 L0750: 10, L0779: 7, L0777: 7, L0731: 7, L0805: 6, L0766: 5, L0770: 4, L0769: 4, L0761: 4, L0776: 4, L0752: 4, L0794: 3, L0751: 3, L0754: 3, H0140: 2, L0803: 2, L0747: 2, L0755: 2, L0759: 2, S0218: 1, H0657: 1, S0282: 1, S0376: 1, H0580: 1, H0734: 1, S0046: 1, H0747: 1, H0392: 1, H0497: 1, H0635: 1, H0575: 1, S0346: 1, S0474: 1, S0049: 1, H0123: 1, L0471: 1, H0024: 1, L0051: 1, H0031: 1, H0412: 1, H0560: 1, S0002: 1, S0426: 1, H0743: 1, L0763: 1, L0772: 1, L0374: 1, L0375: 1, L0806: 1, L0382: 1, L0809: 1, S0126: 1, H0659: 1, S0044: 1, S0190: 1, L0439: 1, L0745: 1, L0756: 1, L0753: 1, L0608: 1 and L0604: 1. 86 HFVHW43 570948 96 H0393: 1 87 HGBER72 826710 97 AR313: 68, AR039: 56, AR299: 36, AR185: 31, AR096: 30, AR300: 28, AR277: 27, AR089: 27, AR219: 25, AR316: 22, AR218: 21, AR104: 20, AR282: 17, AR060: 15, AR240: 14, AR055: 11, AR283: 7, L0766: 12, H0436: 9, H0543: 8, L0769: 6, L0749: 6, L0731: 6, H0556: 5, L0655: 5, S0434: 5, L0439: 4, L0758: 4, S0114: 3, H0255: 3, L3904: 3, L0794: 3, L0776: 3, L0659: 3, L0783: 3, L0809: 3, L0751: 3, H0423: 3, S0358: 2, S0360: 2, S0007: 2, H0549: 2, H0550: 2, H0486: 2, H0014: 2, S0388: 2, H0424: 2, H0031: 2, H0628: 2, L05575: 2, L0771: 2, L0662: 2, L0791: 2, L0793: 2, L2265: 2, L0438: 2, S0328: 2, L0740: 2, L0756: 2, H0265: 1, H0686: 1, S0134: 1, H0657: 1, H0656: 1, S0001: 1, S0418: 1, L0619: 1, S0442: 1, S0408: 1, H0730: 1, H0749: 1, H0619: 1, H0351: 1, S0222: 1, H0592: 1, H0586: 1, T0060: 1, H0250: 1, H0618: 1, H0318: 1, H0052: 1, H0251: 1, H0545: 1, H0569: 1, H0012: 1, H0201: 1, S6028: 1, H0288: 1, H0622: 1, T0023: 1, L0483: 1, H0604: 1, S0036: 1, H0135: 1, H0040: 1, H0264: 1, S0039: 1, L0640: 1, L0763: 1, L0770: 1, L0761: 1, L0648: 1, L0521: 1, L0533: 1, L0774: 1, L0775: 1, L0376: 1, L0378: 1, L0629: 1, L5623: 1, L0666: 1, L0664: 1, S0310: 1, L3811: 1, H0689: 1, H0659: 1, H0660: 1, H0648: 1, H0696: 1, H0576: 1, S0028: 1, L0742: 1, L0750: 1, L0779: 1, L0777: 1, L0752: 1, L0591: 1, L0601: 1, H0542: 1 and H0506: 1. 88 HGBHP91 693011 98 AR313: 32, AR039: 24, AR299: 22, AR089: 21, AR185: 17, AR096: 16, AR060: 15, AR316: 13, AR300: 13, AR277: 13, AR240: 12, AR218: 11, AR055: 11, AR104: 11, AR282: 9, AR219: 9, AR283: 5, H0014: 1 89 HGLBG15 701990 99 AR055: 14, AR162: 7, AR161: 7, AR163: 7, AR104: 6, AR060: 6, AR218: 6, AR191: 6, AR089: 6, AR197: 6, AR261: 6, AR269: 5, AR170: 5, AR176: 5, AR165: 5, AR185: 5, AR188: 5, AR164: 5, AR189: 5, AR291: 5, AR166: 5, AR246: 5, AR190: 5, AR096: 5, AR257: 4, AR240: 4, AR243: 4, AR288: 4, AR309: 4, AR272: 4, AR316: 4, AR275: 4, AR270: 4, AR175: 4, AR290: 4, AR274: 4, AR053: 4, AR219: 4, AR289: 4, AR264: 4, AR255: 4, AR199: 4, AR268: 4, AR204: 4, AR286: 4, AR271: 4, AR039: 4, AR205: 3, AR173: 3, AR196: 3, AR233: 3, AR287: 3, AR262: 3, AR215: 3, AR267: 3, AR300: 3, AR200: 3, AR177: 3, AR296: 3, AR181: 3, AR283: 3, AR299: 3, AR295: 3, AR239: 3, AR311: 3, AR282: 3, AR297: 3, AR174: 3, AR285: 3, AR294: 3, AR293: 3, AR168: 3, AR201: 3, AR238: 3, AR235: 3, AR217: 3, AR313: 3, AR198: 3, AR312: 3, AR258: 3, AR203: 3, AR178: 3, AR254: 3, AR211: 2, AR263: 2, AR247: 2, AR193: 2, AR237: 2, AR266: 2, AR277: 2, AR256: 2, AR182: 2, AR171: 2, AR210: 2, AR250: 2, AR260: 2, AR195: 2, AR172: 2, AR207: 2, AR236: 2, AR232: 2, AR221: 2, AR226: 2, AR224: 2, AR216: 1, AR179: 1, AR033: 1, AR061: 1, AR252: 1, L0803: 19, S0474: 17, L0748: 13, S0408: 11, H0351: 11, L2669: 11, L2504: 10, L0770: 10, L0805: 9, L0439: 9, L0754: 9, S0422: 8, L0809: 8, L0794: 6, L0755: 6, L0731: 6, L0758: 6, S0360: 5, H0265: 4, S0414: 4, H0581: 4, H0271: 4, L0771: 4, L0804: 4, L0776: 4, L0659: 4, L0666: 4, L0749: 4, L0591: 4, H0327: 3, L0806: 3, L0655: 3, L0636: 3, L0565: 3, H0436: 3, L0777: 3, S0434: 3, S0436: 3, S0412: 3, S0116: 2, S0212: 2, H0661: 2, S0358: 2, S0132: 2, L3388: 2, S0222: 2, H0123: 2, H0266: 2, S0003: 2, H0031: 2, H0551: 2, L0598: 2, L0638: 2, L0662: 2, L0766: 2, L0650: 2, L0664: 2, L0665: 2, S0374: 2, H0547: 2, H0435: 2, H0660: 2, S0378: 2, L0740: 2, L0750: 2, L0756: 2, L0752: 2, H0624: 1, H0556: 1, S0040: 1, H0295: 1, S0114: 1, H0656: 1, L2904: 1, S0001: 1, H0671: 1, S0356: 1, S0442: 1, S0376: 1, S0444: 1, H0675: 1, H0730: 1, H0741: 1, H0208: 1, S0045: 1, S0476: 1, H0393: 1, H0550: 1, H0431: 1, H0586: 1, H0642: 1, L3499: 1, H0013: 1, H0069: 1, H0635: 1, H0427: 1, H0156: 1, L0021: 1, H0042: 1, T0082: 1, H0590: 1, S0010: 1, S0318: 1, H0251: 1, H0596: 1, L0040: 1, H0545: 1, H0457: 1, H0009: 1, N0006: 1, L0471: 1, H0024: 1, H0051: 1, H0083: 1, H0061: 1, S0316: 1, H0687: 1, H0688: 1, H0644: 1, H0617: 1, H0591: 1, H0038: 1, H0040: 1, H0616: 1, H0264: 1, H0100: 1, H0561: 1, S0440: 1, L2270: 1, S0426: 1, H0529: 1, L0763: 1, L0637: 1, L0761: 1, L0373: 1, L0646: 1, L0800: 1, L0764: 1, L0626: 1, L0653: 1, L0606: 1, L0661: 1, L0515: 1, L5622: 1, L0789: 1, L0792: 1, L0793: 1, L0663: 1, L2653: 1, L2257: 1, L2259: 1, L2261: 1, L2654: 1, H0144: 1, L0438: 1, H0520: 1, H0519: 1, H0659: 1, H0658: 1, S0328: 1, S0330: 1, S0380: 1, H0710: 1, H0521: 1, H0522: 1, H0696: 1, S0044: 1, S0406: 1, S0027: 1, L0742: 1, L0744: 1, L0751: 1, L0745: 1, L0747: 1, L0779: 1, L0780: 1, L0757: 1, L0759: 1, S0031: 1, S0260: 1, L0596: 1, L0605: 1, L0595: 1, S0026: 1, S0192: 1, S0242: 1, H0542: 1, H0543: 1, S0042: 1 and S0462: 1. 90 HHEAK45 765278 100 AR277: 12, AR283: 11, AR313: 11, AR316: 9, AR282: 9, AR089: 7, AR240: 7, AR104: 7, AR299: 7, AR039: 7, AR218: 6, AR096: 6, AR055: 6, AR300: 6, AR185: 6, AR060: 4, AR219: 3, L0758: 9, L0748: 6, L0747: 6, L0779: 5, L0750: 4, H0556: 3, S0440: 3, H0658: 3, H0656: 2, L0770: 2, L0769: 2, L0804: 2, L0774: 2, H0144: 2, H0648: 2, L0439: 2, L0749: 2, L0596: 2, H0265: 1, S0444: 1, H0318: 1, H0597: 1, H0050: 1, H0024: 1, H0135: 1, H0090: 1, H0038: 1, H0616: 1, H0494: 1, L0065: 1, S0422: 1, H0529: 1, L0637: 1, L0764: 1, L0768: 1, L0794: 1, L0387: 1, L0803: 1, L0805: 1, L0809: 1, L0788: 1, L0790: 1, L0664: 1, L0438: 1, H0555: 1, L0780: 1, L0731: 1, H0444: 1, H0542: 1, H0543: 1 and H0423: 1. 91 HHEOW19 886174 101 AR169: 30, AR089: 25, AR207: 25, AR308: 25, AR214: 24, AR263: 24, AR165: 24, AR264: 24, AR164: 23, AR161: 23, AR168: 23, AR222: 23, AR171: 22, AR283: 22, AR166: 22, AR162: 22, AR311: 21, AR163: 21, AR096: 21, AR223: 21, AR213: 19, AR104: 19, AR316: 19, AR219: 19, AR218: 18, AR217: 18, AR312: 18, AR212: 18, AR225: 17, AR309: 17, AR282: 17, AR313: 17, AR039: 17, AR272: 17, AR299: 16, AR216: 16, AR060: 15, AR172: 15, AR274: 15, AR053: 15, AR170: 15, AR240: 14, AR055: 14, AR185: 14, AR195: 13, AR277: 13, AR197: 13, AR235: 13, AR295: 12, AR192: 12, AR224: 12, AR296: 11, AR297: 11, AR246: 11, AR285: 10, AR198: 10, AR245: 10, AR293: 10, AR252: 10, AR288: 10, AR205: 10, AR300: 10, AR221: 9, AR242: 9, AR287: 9, AR201: 9, AR247: 9, AR253: 9, AR033: 9, AR266: 9, AR215: 9, AR275: 8, AR291: 8, AR174: 8, AR261: 8, AR193: 8, AR243: 8, AR271: 8, AR177: 8, AR270: 8, AR254: 8, AR289: 7, AR236: 7, AR286: 7, AR175: 6, AR204: 6, AR269: 6, AR189: 6, AR294: 6, AR180: 6, AR178: 5, AR250: 5, AR183: 5, AR199: 5, AR257: 5, AR181: 5, AR179: 5, AR268: 5, AR262: 5, AR173: 5, AR290: 5, AR258: 5, AR255: 4, AR061: 4, AR210: 4, AR191: 4, AR190: 4, AR229: 4, AR196: 4, AR176: 4, AR188: 3, AR226: 3, AR239: 3, AR182: 3, AR200: 3, AR234: 3, AR238: 3, AR267: 3, AR232: 3, AR230: 3, AR203: 3, AR256: 3, AR231: 3, AR211: 3, AR237: 3, AR233: 2, AR227: 2, AR260: 2, AR228: 1, L0748: 4, L0745: 4, L0775: 3, L0776: 3, L0758: 3, H0458: 2, H0050: 2, S0003: 2, H0529: 2, L0764: 2, L0747: 2, L0599: 2, L0362: 2, H0556: 1, S0116: 1, S0282: 1, H0662: 1, H0305: 1, S0420: 1, S0444: 1, H0329: 1, H0351: 1, H0411: 1, S0278: 1, H0438: 1, T0039: 1, H0635: 1, H0156: 1, H0235: 1, H0327: 1, L0471: 1, H0428: 1, H0031: 1, H0644: 1, H0032: 1, S0366: 1, H0038: 1, H0616: 1, T0067: 1, H0477: 1, H0059: 1, H0560: 1, H0625: 1, S0422: 1, L0769: 1, L0761: 1, L0667: 1, L0771: 1, L0662: 1, L0806: 1, L0655: 1, L0809: 1, L5622: 1, L0789: 1, L0790: 1, L0665: 1, S0052: 1, H0144: 1, H0520: 1, H0547: 1, H0519: 1, H0435: 1, H0539: 1, S0044: 1, S0392: 1, L0754: 1, L0749: 1, L0750: 1, L0779: 1, L0755: 1, L0759: 1, S0434: 1, L0608: 1, H0543: 1 and S0452: 1. 92 HHFEB79 1300768 102 AR215: 14, AR225: 11, AR316: 9, AR089: 9, AR217: 8, AR221: 8, AR235: 7, AR161: 7, AR162: 7, AR163: 7, AR170: 7, AR039: 7, AR096: 7, AR172: 6, AR216: 6, AR168: 6, AR176: 6, AR183: 6, AR269: 6, AR171: 5, AR055: 5, AR182: 5, AR313: 5, AR299: 5, AR224: 5, AR060: 5, AR233: 5, AR214: 5, AR296: 5, AR180: 4, AR266: 4, AR300: 4, AR282: 4, AR222: 4, AR181: 4, AR104: 4, AR218: 4, AR228: 4, AR290: 4, AR263: 4, AR178: 4, AR173: 4, AR247: 4, AR257: 4, AR270: 4, AR255: 4, AR185: 4, AR237: 4, AR229: 4, AR169: 4, AR165: 4, AR277: 4, AR177: 4, AR268: 4, AR264: 4, AR179: 4, AR311: 4, AR267: 4, AR166: 4, AR240: 4, AR175: 4, AR309: 4, AR200: 3, AR164: 3, AR191: 3, AR061: 3, AR283: 3, AR219: 3, AR236: 3, AR293: 3, AR291: 3, AR231: 3, AR261: 3, AR234: 3, AR288: 3, AR190: 3, AR223: 3, AR294: 3, AR211: 3, AR238: 3, AR262: 3, AR230: 3, AR210: 3, AR287: 3, AR297: 3, AR250: 3, AR239: 3, AR289: 3, AR196: 2, AR203: 2, AR226: 2, AR285: 2, AR053: 2, AR272: 2, AR174: 2, AR286: 2, AR227: 2, AR188: 2, AR254: 2, AR295: 2, AR258: 2, AR275: 2, AR232: 2, AR256: 2, AR189: 2, AR312: 2, AR308: 2, AR212: 2, AR199: 2, AR205: 2, AR260: 2, AR198: 1, AR033: 1, AR274: 1, AR192: 1, H0494: 1 and H0768: 1. HHFEB79 863749 256 93 HHFEC39 609873 103 AR055: 11, AR104: 8, AR060: 8, AR218: 7, AR277: 7, AR096: 6, AR300: 6, AR219: 6, AR299: 5, AR089: 5, AR283: 5, AR316: 5, AR240: 5, AR039: 5, AR185: 4, AR282: 3, AR313: 3, L0805: 21, L0776: 19, L0751: 14, L0759: 13, L0770: 11, H0615: 8, L0803: 8, L0438: 7, L0439: 7, L0758: 7, L0769: 6, L0521: 6, L0754: 6, H0624: 5, H0486: 5, L0500: 5, L0807: 5, L0740: 5, L0591: 5, H0716: 4, H0351: 4, L0774: 4, H0144: 4, S0328: 4, L0748: 4, L0745: 4, L0604: 4, S0414: 3, H0013: 3, S0250: 3, H0428: 3, H0644: 3, H0591: 3, L0659: 3, L0783: 3, L0809: 3, L0791: 3, L0793: 3, L0666: 3, H0670: 3, L0779: 3, L0777: 3, L0731: 3, H0583: 2, S0408: 2, L0717: 2, S0280: 2, S0010: 2, H0052: 2, H0024: 2, T0010: 2, H0594: 2, H0266: 2, H0031: 2, H0032: 2, T0067: 2, L0796: 2, L0662: 2, L0794: 2, L0806: 2, L0518: 2, L0792: 2, L3643: 1, S0342: 1, L0002: 1, H0657: 1, H0255: 1, H0305: 1, H0728: 1, H0733: 1, H0734: 1, S0007: 1, H0645: 1, H0640: 1, H0369: 1, H0261: 1, H0549: 1, H0550: 1, S0222: 1, H0586: 1, T0040: 1, L3655: 1, L0021: 1, L0022: 1, L0105: 1, T0071: 1, L0109: 1, H0194: 1, H0263: 1, H0566: 1, H0050: 1, L0471: 1, H0051: 1, S0051: 1, S0024: 1, H0355: 1, H0510: 1, H0271: 1, H0328: 1, H0039: 1, H0622: 1, L0483: 1, H0124: 1, S0036: 1, H0038: 1, H0616: 1, H0412: 1, H0059: 1, H0100: 1, H0646: 1, S0422: 1, S0002: 1, H0743: 1, H0529: 1, L0520: 1, L0640: 1, L0763: 1, L0773: 1, L0364: 1, L0649: 1, L0497: 1, L0526: 1, L0788: 1, L0789: 1, L0663: 1, L0665: 1, S0374: 1, H0780: 1, H0547: 1, S0126: 1, H0689: 1, H0648: 1, S0330: 1, S0378: 1, H0522: 1, S0037: 1, L0747: 1, L0750: 1, L0780: 1, L0752: 1, H0595: 1, S0434: 1, L0608: 1, L0594: 1, L0361: 1, L0603: 1, S0026: 1, S0192: 1, S0194: 1, H0423: 1, S0398: 1, S0460: 1, H0506: 1, H0008: 1 and H0352: 1. 94 HHFFS40 824059 104 AR219: 22, AR277: 18, AR283: 17, AR218: 16, AR039: 15, AR282: 15, AR089: 14, AR316: 13, AR313: 13, AR096: 12, AR299: 12, AR104: 12, AR240: 10, AR055: 10, AR300: 10, AR185: 9, AR060: 8, S0422: 7, L0748: 6, L0591: 6, L0766: 5, L0754: 5, H0423: 5, S0408: 4, H0069: 4, L0803: 4, L0602: 4, H0657: 3, S0442: 3, S0046: 3, H0596: 3, S0003: 3, H0032: 3, H0169: 3, H0674: 3, L0662: 3, L0794: 3, L0526: 3, H0670: 3, L0740: 3, L0759: 3, S0134: 2, S0212: 2, H0661: 2, S0444: 2, H0046: 2, L0471: 2, H0355: 2, H0038: 2, H0100: 2, L0564: 2, S0440: 2, H0529: 2, L0770: 2, L0769: 2, L0667: 2, L0771: 2, L0521: 2, L0804: 2, L0805: 2, L0384: 2, L0809: 2, L0665: 2, H0659: 2, L0743: 2, L0750: 2, L0731: 2, S0436: 2, L0592: 2, L0599: 2, L0608: 2, L0362: 2, H0171: 1, H0556: 1, H0686: 1, H0713: 1, H0717: 1, H0738: 1, H0740: 1, H0656: 1, H0663: 1, H0662: 1, H0402: 1, S0356: 1, H0742: 1, H0730: 1, H0747: 1, S0222: 1, H0574: 1, H0632: 1, H0486: 1, H0013: 1, H0581: 1, S0049: 1, H0052: 1, H0194: 1, H0309: 1, H0263: 1, H0123: 1, H0050: 1, H0373: 1, H0510: 1, S6028: 1, H0266: 1, H0615: 1, L0483: 1, H0644: 1, L0143: 1, H0708: 1, H0135: 1, H0163: 1, H0090: 1, H0616: 1, T0067: 1, H0488: 1, H0412: 1, H0059: 1, H0494: 1, S0382: 1, S0306: 1, S0450: 1, H0509: 1, H0641: 1, H0647: 1, H0646: 1, L0520: 1, L0763: 1, L0637: 1, L0373: 1, L0363: 1, L5564: 1, L0775: 1, L0375: 1, L0651: 1, L0655: 1, L0661: 1, L0527: 1, L0656: 1, L0659: 1, L0518: 1, L0532: 1, L0663: 1, L0664: 1, S0374: 1, H0682: 1, H0658: 1, H0660: 1, H0672: 1, H0539: 1, H0521: 1, S0044: 1, S0406: 1, H0478: 1, L0744: 1, L0439: 1, L0747: 1, L0779: 1, L0777: 1, L0758: 1, L0480: 1, L0595: 1, H0667: 1, S0192: 1, S0194: 1, S0196: 1, H0422: 1 and S0424: 1. 95 HHGCS78 634605 105 AR277: 76, AR283: 71, AR219: 57, AR218: 56, AR316: 56, AR089: 52, AR313: 52, AR240: 51, AR055: 45, AR282: 45, AR299: 44, AR104: 41, AR096: 41, AR185: 34, AR039: 33, AR060: 31, AR300: 30, L0770: 7, H0333: 3, L0783: 2, L0731: 2, H0445: 2, S0418: 1, H0741: 1, S0002: 1, L0369: 1, L0643: 1, L0764: 1, L0794: 1, L0803: 1, L0775: 1, L0375: 1, L0378: 1, L0655: 1, L0809: 1, L0666: 1, L0664: 1, L0754: 1, L0747: 1, L0749: 1, L0752: 1 and L0591: 1. 96 HHPFP26 753269 106 AR219: 14, AR218: 13, AR313: 11, AR299: 8, AR089: 8, AR185: 7, AR316: 7, AR039: 6, AR096: 6, AR300: 6, AR055: 6, AR060: 4, AR104: 4, AR282: 3, AR240: 2, AR283: 2, AR277: 2, L0766: 4, H0441: 3, S0422: 3, L0750: 3, L0752: 3, L0755: 3, H0624: 2, S0360: 2, L0771: 2, L0662: 2, L0794: 2, L0803: 2, L0804: 2, L0776: 2, L0791: 2, L0666: 2, S0406: 2, L0439: 2, L0731: 2, L0758: 2, S0194: 2, H0170: 1, L3388: 1, H0411: 1, H0486: 1, L0163: 1, H0051: 1, H0551: 1, H0625: 1, L0381: 1, L0650: 1, L0659: 1, L0518: 1, L0790: 1, L0793: 1, H0519: 1, H0659: 1, S0380: 1, S0013: 1, L0747: 1, L0777: 1, L0591: 1, L0608: 1 and H0422: 1. 97 HHPFU28 824573 107 AR218: 11, AR039: 9, AR219: 9, AR104: 8, AR300: 8, AR185: 7, AR055: 6, AR299: 6, AR089: 6, AR096: 6, AR240: 6, AR060: 5, AR282: 5, AR316: 5, AR313: 4, AR277: 3, AR283: 3, L0622: 2, L0518: 2, L0382: 2, L0663: 2, L0750: 2, L0752: 2, L0362: 2, S0114: 1, S0420: 1, S0354: 1, S0444: 1, S0222: 1, S0010: 1, H0046: 1, H0051: 1, L0483: 1, H0644: 1, H0412: 1, H0529: 1, L0794: 1, L0561: 1, L0666: 1, S0330: 1, S0028: 1, L0779: 1, L0777: 1, L0758: 1, S0031: 1, H0444: 1 and L0592: 1. 98 HHSBI06 639097 108 AR218: 14, AR060: 11, AR282: 11, AR055: 11, AR089: 10, AR219: 10, AR185: 10, AR277: 10, AR039: 9, AR104: 9, AR299: 8, AR316: 8, AR300: 8, AR313: 8, AR283: 7, AR096: 7, AR240: 5, L0766: 12, L0794: 7, L0439: 7, L0749: 7, L0803: 6, L0740: 6, L0745: 6, H0052: 5, L0754: 5, L3181: 4, L0770: 4, L0666: 4, L0748: 4, H0553: 3, L0790: 3, L0589: 3, H0543: 3, S0114: 2, S0134: 2, H0650: 2, S0354: 2, S0444: 2, H0747: 2, S0476: 2, H0393: 2, H0549: 2, H0586: 2, H0013: 2, H0599: 2, H0014: 2, S0051: 2, S0003: 2, H0032: 2, H0674: 2, H0135: 2, S0142: 2, L0372: 2, L0800: 2, L0764: 2, L0805: 2, L0655: 2, L0657: 2, L0659: 2, L0809: 2, L0789: 2, L0792: 2, H0144: 2, L0438: 2, H0684: 2, H0658: 2, H0539: 2, H0521: 2, S0406: 2, S0028: 2, L0750: 2, L0779: 2, L0777: 2, L0752: 2, L0731: 2, L0758: 2, S0436: 2, H0653: 2, H0542: 2, H0556: 1, H0716: 1, H0381: 1, S0116: 1, H0661: 1, S0356: 1, S0442: 1, S0360: 1, H0675: 1, H0734: 1, L2255: 1, L3726: 1, H0261: 1, S0222: 1, L3499: 1, T0114: 1, H0706: 1, H0036: 1, H0318: 1, H0581: 1, L0738: 1, H0123: 1, H0620: 1, S0050: 1, H0015: 1, H0051: 1, H0355: 1, H0416: 1, H0286: 1, H0328: 1, H0428: 1, H0622: 1, T0006: 1, H0030: 1, H0031: 1, H0644: 1, H0617: 1, L0055: 1, H0124: 1, H0163: 1, H0038: 1, H0040: 1, H0616: 1, H0551: 1, H0264: 1, H0102: 1, S0112: 1, L0564: 1, H0280: 1, H0494: 1, H0561: 1, S0440: 1, H0633: 1, L3815: 1, S0002: 1, L0763: 1, L0769: 1, L0761: 1, L0646: 1, L0642: 1, L0644: 1, L0645: 1, L0648: 1, L0662: 1, L0363: 1, L0775: 1, L0375: 1, L0651: 1, L0784: 1, L0806: 1, L0653: 1, L0807: 1, L0658: 1, L0540: 1, L5622: 1, L0368: 1, L0665: 1, L2655: 1, L2257: 1, L2263: 1, L2258: 1, L2262: 1, S0374: 1, H0723: 1, L3811: 1, L2670: 1, H0547: 1, L3215: 1, H0648: 1, H0672: 1, S0328: 1, H0753: 1, H0522: 1, H0436: 1, S0392: 1, H0626: 1, L0759: 1, S0031: 1, H0445: 1, S0434: 1, L0596: 1, L0588: 1, S0192: 1, H0423: 1, S0424: 1 and H0352: 1. 99 HHSBI65 801910 109 AR176: 10, AR216: 9, AR217: 8, AR168: 8, AR169: 8, AR182: 8, AR161: 8, AR196: 8, AR162: 8, AR214: 8, AR228: 8, AR269: 8, AR231: 8, AR233: 7, AR171: 7, AR207: 7, AR229: 7, AR181: 7, AR223: 7, AR163: 7, AR198: 7, AR165: 7, AR172: 7, AR225: 7, AR267: 7, AR224: 7, AR266: 6, AR268: 6, AR170: 6, AR164: 6, AR237: 6, AR221: 6, AR222: 6, AR177: 6, AR179: 6, AR235: 6, AR270: 6, AR183: 6, AR204: 6, AR288: 6, AR053: 6, AR239: 6, AR193: 5, AR236: 5, AR250: 5, AR191: 5, AR264: 5, AR293: 5, AR296: 5, AR055: 5, AR238: 5, AR247: 5, AR309: 5, AR300: 5, AR178: 5, AR295: 5, AR290: 5, AR294: 5, AR060: 5, AR061: 5, AR287: 5, AR257: 5, AR201: 5, AR282: 5, AR291: 5, AR175: 5, AR311: 4, AR261: 4, AR234: 4, AR289: 4, AR275: 4, AR262: 4, AR252: 4, AR242: 4, AR213: 4, AR253: 4, AR297: 4, AR203: 4, AR277: 4, AR180: 4, AR212: 4, AR200: 4, AR316: 4, AR286: 4, AR274: 4, AR255: 4, AR312: 4, AR240: 4, AR174: 4, AR215: 4, AR039: 4, AR192: 4, AR263: 4, AR205: 4, AR283: 3, AR232: 3, AR271: 3, AR285: 3, AR190: 3, AR226: 3, AR185: 3, AR033: 3, AR246: 3, AR230: 3, AR188: 3, AR308: 3, AR227: 3, AR096: 3, AR173: 3, AR313: 3, AR089: 3, AR195: 3, AR272: 3, AR199: 3, AR189: 3, AR260: 3, AR197: 3, AR299: 3, AR104: 2, AR210: 2, AR258: 2, AR211: 2, AR256: 2, AR243: 2, AR218: 2, AR219: 2, L0439: 7, L0794: 5, L0766: 5, S0354: 2, H0549: 2, S0051: 2, S0142: 2, L0372: 2, L0809: 2, L0438: 2, H0658: 2, H0650: 1, H0381: 1, S0116: 1, S0356: 1, S0360: 1, H0261: 1, H0586: 1, H0486: 1, H0036: 1, H0052: 1, L0738: 1, H0457: 1, H0014: 1, H0051: 1, H0617: 1, H0032: 1, H0561: 1, S0440: 1, H0633: 1, L0763: 1, L0761: 1, L0800: 1, L0644: 1, L0645: 1, L0764: 1, L0648: 1, L0655: 1, L0657: 1, L0658: 1, L0368: 1, L0665: 1, L3811: 1, S0044: 1, S0406: 1, H0626: 1, L0731: 1, S0434: 1, S0436: 1, H0653: 1 and H0423: 1. 100 HISAT67 843549 110 AR283: 20, AR282: 15, AR277: 11, AR089: 11, AR219: 11, AR299: 10, AR218: 10, AR316: 9, AR313: 8, AR096: 8, AR185: 8, AR104: 7, AR240: 7, AR055: 6, AR060: 6, AR039: 6, AR300: 6, L0751: 8, L0754: 6, L0731: 6, H0556: 5, L0766: 5, L0439: 5, L0750: 5, L0770: 4, L0666: 4, H0521: 4, S0356: 3, H0052: 3, H0424: 3, L0776: 3, S0406: 3, S0418: 2, S0442: 2, H0580: 2, H0733: 2, H0486: 2, H0575: 2, S0438: 2, L0769: 2, L3905: 2, L0659: 2, L0663: 2, L0665: 2, L0748: 2, L0749: 2, S0436: 2, T0002: 1, H0159: 1, S6024: 1, S0134: 1, H0656: 1, H0484: 1, S0358: 1, S0360: 1, H0742: 1, S0046: 1, H0393: 1, S0278: 1, H0607: 1, H0586: 1, H0642: 1, H0632: 1, H0427: 1, L0021: 1, H0599: 1, H0318: 1, H0746: 1, H0194: 1, L0738: 1, H0178: 1, H0566: 1, H0051: 1, T0010: 1, H0408: 1, H0290: 1, H0328: 1, H0401: 1, H0417: 1, H0553: 1, H0617: 1, H0040: 1, H0264: 1, H0623: 1, H0059: 1, T0041: 1, H0494: 1, H0561: 1, H0509: 1, S0144: 1, L0763: 1, L0638: 1, L5565: 1, L0772: 1, L0373: 1, L0764: 1, L0662: 1, L0626: 1, L0363: 1, L0649: 1, L0650: 1, L0774: 1, L0806: 1, L0654: 1, L0789: 1, L0664: 1, L3822: 1, H0699: 1, S0374: 1, L3828: 1, H0547: 1, H0689: 1, H0659: 1, H0658: 1, H0670: 1, H0672: 1, H0539: 1, L0740: 1, L0746: 1, L0752: 1, L0755: 1, L0757: 1, L0584: 1, L0596: 1, L0608: 1 and H0352: 1. 101 HISBA38 561711 111 AR277: 1, L0766: 3, H0318: 1 and H0539: 1. 102 HJBCU75 638329 112 AR162: 12, AR161: 12, AR163: 11, AR186: 10, AR244: 10, AR273: 8, AR222: 8, AR225: 8, AR221: 8, AR214: 8, AR216: 8, AR224: 7, AR223: 7, AR282: 7, AR215: 7, AR052: 7, AR202: 7, AR200: 6, AR206: 6, AR176: 6, AR269: 6, AR235: 6, AR272: 6, AR217: 6, AR055: 6, AR182: 6, AR264: 6, AR275: 6, AR061: 6, AR183: 5, AR168: 5, AR171: 5, AR309: 5, AR270: 5, AR228: 5, AR290: 5, AR268: 5, AR310: 5, AR181: 5, AR257: 5, AR060: 5, AR255: 5, AR165: 5, AR191: 5, AR164: 5, AR274: 5, AR247: 5, AR246: 4, AR166: 4, AR178: 4, AR311: 4, AR291: 4, AR312: 4, AR236: 4, AR173: 4, AR249: 4, AR233: 4, AR240: 4, AR288: 4, AR174: 4, AR267: 4, AR239: 4, AR204: 4, AR185: 4, AR287: 4, AR172: 4, AR192: 4, AR297: 4, AR213: 4, AR194: 4, AR177: 4, AR294: 4, AR261: 4, AR184: 4, AR190: 4, AR170: 3, AR284: 3, AR262: 3, AR210: 3, AR188: 3, AR089: 3, AR313: 3, AR196: 3, AR298: 3, AR266: 3, AR175: 3, AR033: 3, AR260: 3, AR285: 3, AR189: 3, AR316: 3, AR231: 3, AR251: 3, AR293: 3, AR296: 3, AR237: 3, AR286: 3, AR265: 3, AR243: 3, AR277: 3, AR300: 3, AR039: 3, AR289: 3, AR315: 3, AR179: 3, AR271: 3, AR234: 3, AR263: 3, AR199: 3, AR283: 3, AR203: 3, AR096: 3, AR299: 3, AR295: 3, AR229: 3, AR230: 3, AR292: 3, AR180: 3, AR104: 2, AR198: 2, AR308: 2, AR219: 2, AR053: 2, AR218: 2, AR211: 2, AR205: 2, AR238: 2, AR241: 2, AR258: 2, AR256: 2, AR226: 2, AR232: 2, AR280: 2, AR169: 1, AR227: 1, AR259: 1, AR201: 1, L0805: 3, H0556: 2, H0046: 2, S0022: 2, L0764: 2, L0662: 2, L0748: 2, H0013: 1, H0050: 1, H0039: 1, H0040: 1, H0087: 1, T0042: 1, L0643: 1, L0794: 1, L0803: 1, L0804: 1, L0807: 1, L0809: 1, L0666: 1, H0144: 1, L0749: 1, L0779: 1 and L0758: 1. 103 HJMAA03 824062 113 AR207: 12, AR309: 11, AR192: 11, AR252: 10, AR053: 9, AR212: 9, AR242: 9, AR235: 9, AR213: 8, AR215: 8, AR198: 8, AR170: 8, AR169: 8, AR161: 8, AR162: 8, AR253: 8, AR223: 8, AR165: 8, AR166: 8, AR263: 7, AR163: 7, AR164: 7, AR274: 7, AR224: 7, AR245: 7, AR264: 7, AR214: 7, AR195: 7, AR217: 7, AR174: 7, AR197: 7, AR261: 7, AR311: 7, AR221: 7, AR282: 6, AR308: 6, AR222: 6, AR240: 6, AR312: 6, AR205: 6, AR171: 6, AR168: 6, AR193: 6, AR313: 6, AR246: 6, AR177: 6, AR173: 6, AR277: 6, AR216: 6, AR247: 6, AR180: 6, AR225: 6, AR283: 5, AR269: 5, AR300: 5, AR089: 5, AR201: 5, AR272: 5, AR297: 5, AR189: 5, AR204: 5, AR183: 5, AR299: 5, AR175: 5, AR288: 5, AR176: 5, AR295: 5, AR271: 5, AR250: 5, AR096: 5, AR275: 5, AR270: 4, AR316: 4, AR196: 4, AR191: 4, AR286: 4, AR178: 4, AR290: 4, AR185: 4, AR268: 4, AR296: 4, AR291: 4, AR257: 4, AR033: 4, AR199: 4, AR181: 4, AR039: 4, AR236: 4, AR229: 4, AR243: 4, AR285: 4, AR254: 4, AR289: 4, AR238: 3, AR172: 3, AR293: 3, AR262: 3, AR190: 3, AR287: 3, AR179: 3, AR200: 3, AR055: 3, AR104: 3, AR060: 3, AR188: 3, AR239: 3, AR182: 3, AR233: 3, AR258: 3, AR294: 3, AR061: 3, AR237: 3, AR231: 3, AR234: 3, AR226: 3, AR203: 3, AR255: 3, AR232: 3, AR230: 2, AR211: 2, AR227: 2, AR228: 2, AR267: 2, AR210: 2, AR266: 2, AR219: 2, AR260: 1, AR218: 1, AR256: 1, L0749: 8, L0803: 5, L0748: 5, L0777: 5, L0794: 4, L0766: 4, L0804: 4, H0135: 3, H0551: 3, L0754: 3, L0599: 3, H0542: 3, H0556: 2, H0545: 2, H0674: 2, L0764: 2, L0774: 2, L0776: 2, L0655: 2, H0521: 2, L0439: 2, L0752: 2, L0731: 2, L0596: 2, H0395: 1, H0713: 1, H0483: 1, H0663: 1, S0358: 1, H0580: 1, H0329: 1, S0045: 1, H0453: 1, H0427: 1, H0599: 1, H0706: 1, H0150: 1, H0123: 1, L0471: 1, L0163: 1, H0051: 1, H0275: 1, S0003: 1, S0214: 1, H0628: 1, H0090: 1, H0040: 1, H0087: 1, T0067: 1, H0412: 1, H0494: 1, H0509: 1, H0633: 1, H0647: 1, S0344: 1, L0769: 1, L0637: 1, L0761: 1, L0772: 1, L0800: 1, L0374: 1, L0771: 1, L0363: 1, L0768: 1, L0806: 1, L0659: 1, L0382: 1, L0809: 1, L0545: 1, L0789: 1, L0666: 1, H0519: 1, H0659: 1, S0152: 1, S0404: 1, L0751: 1, L0747: 1, L0750: 1, L0779: 1, S0436: 1, L0608: 1, S0276: 1, H0543: 1, H0506: 1 and H0352: 1. 104 HJPCH08 840365 114 AR277: 9, AR055: 9, AR218: 8, AR060: 6, AR219: 6, AR283: 5, AR300: 5, AR104: 5, AR240: 5, AR316: 5, AR185: 5, AR313: 5, AR299: 4, AR089: 3, AR096: 3, AR039: 3, AR282: 2, L0758: 9, L0777: 8, H0618: 6, L0794: 6, L0749: 6, L0774: 4, L0748: 4, L0750: 4, S0418: 3, S0358: 3, H0266: 3, L0770: 3, L0766: 3, L0759: 3, S0360: 2, H0150: 2, H0087: 2, L0369: 2, L0769: 2, L0771: 2, L0789: 2, L0663: 2, L0665: 2, H0422: 2, H0556: 1, H0295: 1, H0370: 1, H0331: 1, H0013: 1, L0021: 1, L0022: 1, H0253: 1, H0052: 1, H0204: 1, H0544: 1, H0012: 1, H0620: 1, H0024: 1, H0083: 1, H0510: 1, H0416: 1, H0252: 1, H0424: 1, H0617: 1, L0564: 1, H0494: 1, S0144: 1, L0372: 1, L0646: 1, L0800: 1, L0641: 1, L0764: 1, L0649: 1, L0803: 1, L0650: 1, L0775: 1, L0776: 1, L0655: 1, L0659: 1, L0809: 1, L0666: 1, L0664: 1, H0144: 1, H0521: 1, H0436: 1, S3012: 1, L0747: 1, L0786: 1, L0757: 1, L0608: 1 and L0595: 1. 105 HKABU43 838573 115 AR219: 2, AR282: 1, AR300: 1, AR316: 1, L0794: 7, L0803: 3, H0052: 2, S0250: 2, H0032: 2, H0494: 2, H0529: 2, L0666: 2, L0663: 2, L0747: 2, L0759: 2, H0657: 1, H0664: 1, H0662: 1, S0442: 1, H0741: 1, H0735: 1, H0733: 1, S0046: 1, H0640: 1, H0331: 1, H0559: 1, T0039: 1, H0013: 1, S0280: 1, H0318: 1, T0110: 1, H0024: 1, S0364: 1, H0591: 1, H0038: 1, H0040: 1, S0142: 1, L0640: 1, L0667: 1, L0764: 1, L0662: 1, L0804: 1, L0659: 1, L0517: 1, L0789: 1, L4559: 1, L0664: 1, S0126: 1, H0435: 1, H0539: 1, S0152: 1, H0521: 1, H0522: 1, S0027: 1, L0779: 1, L0758: 1, L0485: 1, L0601: 1, S0026: 1, H0667: 1, S0192: 1, H0542: 1 and H0506: 1. 106 HKIXC44 716213 116 AR104: 28, AR055: 19, AR240: 15, AR219: 11, AR218: 11, AR185: 10, AR060: 9, AR299: 7, AR089: 7, AR283: 7, AR282: 6, AR096: 5, AR316: 5, AR300: 5, AR313: 5, AR039: 4, AR277: 3, L0770: 7, L0742: 5, L0439: 4, L0776: 3, S0358: 2, H0619: 2, S0222: 2, L0769: 2, L0638: 2, L0796: 2, L0805: 2, H0593: 2, L0753: 2, L0485: 2, L0608: 2, H0329: 1, H0351: 1, H0441: 1, H0611: 1, H0370: 1, H0013: 1, H0196: 1, H0052: 1, H0251: 1, H0041: 1, H0024: 1, H0622: 1, S0366: 1, H0623: 1, L0648: 1, L0523: 1, L0806: 1, L0788: 1, L0666: 1, L0663: 1, H0648: 1, H0539: 1, S0152: 1, L0612: 1, L0777: 1, L0599: 1 and S0242: 1. 107 HKTAB41 695732 117 AR277: 83, AR283: 74, AR219: 65, AR313: 56, AR316: 50, AR089: 49, AR218: 47, AR282: 46, AR104: 45, AR055: 42, AR185: 41, AR299: 40, AR096: 35, AR039: 31, AR240: 31, AR060: 26, AR300: 25, L0794: 5, H0574: 1 and H0239: 1. 108 HLDBG17 855953 118 AR313: 205, AR096: 153, AR240: 136, AR282: 133, AR219: 128, AR218: 116, AR299: 111, AR316: 101, AR277: 94, AR089: 89, AR039: 84, AR300: 83, AR283: 82, AR185: 77, AR060: 59, AR104: 50, AR055: 37, L0581: 185, H0509: 97, H0510: 36, H0014: 25, H0355: 18, H0393: 14, L0748: 13, H0574: 12, H0331: 9, H0057: 5, H0144: 5, H0015: 3, L0605: 3, H0357: 2, H0427: 2, L0663: 2, L0749: 2, L0756: 2, H0662: 1, H0351: 1, H0349: 1, H0047: 1, H0038: 1, L0521: 1, L0518: 1, L0809: 1, L0787: 1, L0438: 1, L0439: 1, L0747: 1, L0759: 1 and S0412: 1. 109 HLDQU79 740755 119 AR253: 8, AR171: 7, AR245: 6, AR243: 5, AR183: 5, AR263: 5, AR264: 4, AR250: 4, AR269: 4, AR060: 4, AR180: 4, AR270: 4, AR309: 4, AR162: 4, AR268: 4, AR161: 4, AR165: 4, AR192: 4, AR176: 4, AR164: 4, AR055: 4, AR163: 4, AR213: 4, AR195: 4, AR271: 4, AR166: 3, AR275: 3, AR240: 3, AR282: 3, AR312: 3, AR246: 3, AR178: 3, AR181: 3, AR311: 3, AR168: 3, AR289: 3, AR182: 3, AR193: 3, AR217: 3, AR179: 3, AR212: 3, AR237: 3, AR238: 3, AR299: 3, AR199: 3, AR252: 3, AR229: 3, AR242: 2, AR185: 2, AR300: 2, AR277: 2, AR175: 2, AR293: 2, AR257: 2, AR308: 2, AR177: 2, AR198: 2, AR061: 2, AR214: 2, AR174: 2, AR104: 2, AR231: 2, AR316: 2, AR201: 2, AR233: 2, AR230: 2, AR224: 2, AR236: 2, AR239: 2, AR228: 2, AR188: 2, AR223: 2, AR189: 2, AR247: 2, AR294: 2, AR226: 2, AR266: 2, AR221: 2, AR285: 2, AR191: 2, AR089: 2, AR216: 2, AR200: 2, AR207: 2, AR272: 2, AR232: 2, AR190: 2, AR290: 2, AR283: 2, AR096: 2, AR222: 2, AR296: 2, AR039: 2, AR267: 2, AR205: 2, AR211: 1, AR196: 1, AR173: 1, AR033: 1, AR218: 1, AR295: 1, AR255: 1, AR262: 1, AR215: 1, AR227: 1, AR254: 1, AR234: 1, AR313: 1, AR203: 1, AR256: 1, AR169: 1, AR225: 1, AR210: 1, AR170: 1, L0748: 9, L0731: 7, L0771: 6, L0759: 6, H0013: 5, L0764: 4, L0747: 4, L0758: 4, H0265: 3, H0039: 3, H0038: 3, L0769: 3, L0766: 3, L0775: 3, H0144: 3, L0755: 3, S0444: 2, S0476: 2, H0318: 2, H0050: 2, L0471: 2, H0266: 2, L0374: 2, L0649: 2, L0805: 2, L0663: 2, L0664: 2, H0547: 2, S0126: 2, H0670: 2, L0740: 2, L0754: 2, L0750: 2, L0593: 2, H0667: 2, H0170: 1, H0171: 1, H0685: 1, H0662: 1, S0354: 1, S0360: 1, H0580: 1, H0728: 1, H0151: 1, H0747: 1, L3388: 1, H0357: 1, H0586: 1, H0331: 1, H0574: 1, H0635: 1, H0575: 1, H0263: 1, H0596: 1, H0545: 1, H0012: 1, H0620: 1, H0350: 1, H0355: 1, H0510: 1, H0428: 1, H0604: 1, H0031: 1, H0553: 1, S0366: 1, H0040: 1, H0063: 1, H0059: 1, H0560: 1, H0561: 1, S0440: 1, S0422: 1, H0529: 1, L0640: 1, L0637: 1, L0761: 1, L0772: 1, L0646: 1, L4556: 1, L0774: 1, L0375: 1, L0653: 1, L0382: 1, L5622: 1, L0793: 1, L4501: 1, H0723: 1, L0352: 1, S0152: 1, S0350: 1, H0521: 1, H0696: 1, S0044: 1, H0627: 1, S0027: 1, L0749: 1, L0752: 1, H0595: 1, S0436: 1, L0591: 1, L0595: 1, L0361: 1, S0011: 1, S0194: 1, S0276: 1 and H0423: 1. HLDQU79 837599 257 110 HLHAP05 638476 120 L0005: 3, H0024: 2, H0209: 1 and H0445: 1. 111 HLHBS54 837503 121 AR313: 24, AR039: 20, AR219: 18, AR277: 17, AR089: 17, AR185: 16, AR218: 16, AR096: 15, AR299: 14, AR240: 12, AR104: 11, AR316: 10, AR300: 10, AR282: 9, AR060: 9, AR055: 8, AR283: 7, L0751: 11, L0757: 9, L0595: 8, H0024: 6, S0002: 6, H0545: 5, L0740: 5, S0434: 5, H0620: 4, H0135: 4, S0426: 4, L0776: 4, L0659: 4, L0747: 4, L0750: 4, S0436: 4, H0333: 3, H0046: 3, H0012: 3, H0622: 3, H0087: 3, S0144: 3, L0770: 3, L0809: 3, S0152: 3, S0037: 3, L0754: 3, L0752: 3, S0001: 2, S0360: 2, S0007: 2, H0549: 2, S0222: 2, H0587: 2, H0632: 2, H0618: 2, H0309: 2, H0050: 2, H0266: 2, H0124: 2, H0413: 2, S0344: 2, L0769: 2, L3905: 2, L0772: 2, L0648: 2, L0662: 2, L0517: 2, L0666: 2, L0664: 2, H0689: 2, H0521: 2, H0522: 2, H0696: 2, S0406: 2, L0743: 2, L0744: 2, L0749: 2, L0731: 2, L0589: 2, L0592: 2, L0593: 2, H0149: 1, H0717: 1, S0116: 1, H0484: 1, H0255: 1, H0661: 1, H0662: 1, S0410: 1, H0729: 1, H0728: 1, S0045: 1, S0046: 1, H0619: 1, S0278: 1, H0437: 1, H0550: 1, H0441: 1, H0249: 1, L3653: 1, H0427: 1, H0253: 1, H0052: 1, H0251: 1, H0597: 1, H0544: 1, H0546: 1, L0041: 1, H0041: 1, H0009: 1, H0172: 1, H0566: 1, H0399: 1, H0239: 1, H0687: 1, H0288: 1, H0292: 1, T0023: 1, H0424: 1, H0213: 1, H0617: 1, H0673: 1, H0169: 1, H0376: 1, H0623: 1, S0210: 1, L0369: 1, L0762: 1, L0763: 1, L5565: 1, L0767: 1, L0803: 1, L0775: 1, L0523:, L0806: 1, L0655: 1, L0518: 1, L0783: 1, L0519: 1, L0790: 1, L0663: 1, S0148: 1, S0310: 1, L3811: 1, H0547: 1, H0659: 1, H0651: 1, H0626: 1, S3014: 1, S0027: 1, L0748: 1, L0439: 1, L0777: 1, L0755: 1, L0758: 1, L0759: 1, L0603: 1, H0668: 1, S0196: 1, S0424: 1 and H0352: 1. 112 HLHCS23 560663 122 AR055: 5, AR060: 4, AR185: 3, AR218: 3, AR240: 3, AR300: 3, AR282: 3, AR299: 2, AR039: 2, AR283: 2, AR089: 2, AR219: 2, AR316: 2, AR104: 2, AR096: 1, AR277: 1, H0024: 1 113 HLICE88 840321 123 AR185: 21, AR240: 19, AR104: 13, AR039: 13, AR060: 13, AR089: 13, AR300: 12, AR282: 11, AR096: 11, AR055: 10, AR316: 10, AR219: 10, AR218: 9, AR299: 7, AR283: 7, AR313: 7, AR277: 4, H0014: 72, L3388: 60, H0509: 49, L0581: 44, H0355: 43, H0574: 32, H0393: 30, H0632: 21, H0510: 18, S0438: 18, H0098: 15, H0144: 14, H0331: 13, H0015: 8, L0748: 8, H0722: 7, L3387: 7, H0741: 5, H0013: 5, H0147: 4, T0078: 4, L0615: 3, H0357: 3, S0440: 3, H0730: 2, H0349: 2, H0350: 2, H0057: 2, H0644: 2, H0647: 2, L0605: 2, L0599: 2, H0170: 1, L0448: 1, H0149: 1, L0393: 1, S0444: 1, L3645: 1, H0749: 1, L2255: 1, H0351: 1, H0642: 1, H0427: 1, H0003: 1, H0575: 1, H0199: 1, H0040: 1, H0745: 1, L0787: 1, L0747: 1 and S0436: 1. 114 HLQAS12 886180 124 AR240: 8, AR218: 5, AR316: 4, AR060: 4, AR104: 4, AR055: 3, AR300: 3, AR282: 2, AR185: 2, AR039: 2, AR283: 2, AR299: 2, AR089: 1, AR277: 1, AR313: 1, AR096: 1, H0521: 109, H0271: 18, L0659: 17, L0757: 16, H0494: 15, H0522: 14, S0027: 14, L0740: 12, L0754: 12, L0747: 12, H0556: 11, H0638: 9, S0045: 8, H0250: 8, H0599: 8, S0126: 8, H0265: 7, S0360: 7, S0140: 7, T0040: 7, H0581: 7, S0002: 7, L0666: 7, S0028: 7, S0358: 6, H0635: 6, H0545: 6, H0056: 6, L0663: 6, H0539: 6, L0731: 6, S0132: 5, H0190: 5, H0052: 5, H0266: 5, L0770: 5, S3014: 5, L0590: 5, H0294: 4, S0354: 4, S0278: 4, H0433: 4, H0413: 4, H0100: 4, L0764: 4, L0662: 4, L0776: 4, L0758: 4, H0222: 3, H0295: 3, S0212: 3, H0427: 3, H0575: 3, H0590: 3, S0049: 3, H0544: 3, H0051: 3, S0250: 3, H0622: 3, H0163: 3, H0634: 3, H0412: 3, H0641: 3, S0142: 3, S0344: 3, S0426: 3, L0769: 3, L0771: 3, L0794: 3, L0804: 3, L0655: 3, H0672: 3, L0602: 3, H0555: 3, H0436: 3, S0390: 3, L0751: 3, L0756: 3, S0192: 3, H0506: 3, L0600: 3, H0341: 2, S0418: 2, S0420: 2, S0376: 2, S0468: 2, H0208: 2, S0046: 2, H0392: 2, T0039: 2, T0060: 2, H0191: 2, H0156: 2, H0546: 2, H0247: 2, H0416: 2, H0615: 2, H0039: 2, L0483: 2, H0628: 2, H0032: 2, H0211: 2, H0124: 2, H0087: 2, H0623: 2, S0144: 2, L0598: 2, L0763: 2, L0646: 2, L0773: 2, L0774: 2, L0775: 2, L0806: 2, S0428: 2, S0328: 2, S0037: 2, S0032: 2, L0741: 2, L0743: 2, L0752: 2, L0591: 2, L0608: 2, L0601: 2, L0603: 2, S0194: 2, H0542: 2, H0170: 1, H0171: 1, L3644: 1, H0650: 1, S0116: 1, H0255: 1, H0661: 1, H0580: 1, H0411: 1, S0220: 1, H0331: 1, H0486: 1, L3655: 1, H0069: 1, H0075: 1, L0021: 1, H0002: 1, H0036: 1, H0253: 1, T0048: 1, H0505: 1, H0318: 1, H0023: 1, H0083: 1, S6028: 1, L0669: 1, S0314: 1, H0417: 1, H0316: 1, H0598: 1, H0135: 1, H0063: 1, H0551: 1, H0379: 1, H0268: 1, H0059: 1, T0004: 1, H0561: 1, S0450: 1, H0509: 1, H0649: 1, H0538: 1, S0210: 1, L0761: 1, L0667: 1, L0372: 1, L0648: 1, L0363: 1, L0768: 1, L0381: 1, L0388: 1, L0522: 1, L0784: 1, L0632: 1, L0378: 1, L0656: 1, L0783: 1, L0382: 1, L0532: 1, L0664: 1, L0665: 1, S0052: 1, L0565: 1, H0547: 1, H0519: 1, H0689: 1, H0682: 1, H0670: 1, H0518: 1, S0044: 1, H0576: 1, L0439: 1, L0746: 1, L0755: 1, H0595: 1, S0436: 1, L0581: 1, H0667: 1 and H0352: 1. 115 HLYAR30 781249 125 AR277: 25, AR313: 24, AR283: 17, AR316: 15, AR089: 14, AR299: 14, AR282: 13, AR104: 12, AR096: 11, AR219: 11, AR218: 10, AR039: 10, AR185: 10, AR240: 10, AR300: 10, AR055: 9, AR060: 7, L0759: 4, L0657: 3, L0789: 3, L0439: 3, L0752: 3, L0758: 3, S0360: 2, L0805: 2, L0438: 2, L0750: 2, L0777: 2, H0423: 2, H0171: 1, H0638: 1, H0351: 1, H0178: 1, H0606: 1, L0625: 1, L0769: 1, L0771: 1, L0662: 1, L0794: 1, L0803: 1, L0804: 1, L0650: 1, L0774: 1, L0659: 1, L0809: 1, L0663: 1, H0436: 1, L0748: 1, L0740: 1, H0445: 1, L0604: 1 and H0422: 1. 116 HLYDF73 566869 126 AR277: 12, AR283: 9, AR282: 6, AR316: 6, AR300: 5, AR055: 5, AR089: 5, AR104: 4, AR299: 4, AR185: 4, AR096: 4, AR218: 4, AR313: 4, AR240: 4, AR039: 3, AR219: 3, AR060: 2, H0445: 1 117 HLYDO73 584787 127 H0445: 1 118 HLYGY91 658703 128 AR313: 6, AR316: 5, AR218: 3, AR300: 3, AR299: 3, AR055: 3, AR185: 2, AR039: 2, AR096: 2, AR277: 2, AR219: 1, AR089: 1 H0692: 10, L0777: 10, L0805: 5, L0803: 3, L2497: 2, H0328: 2, L0662: 2, L0794: 2, L0809: 2, L3832: 2, L0748: 2, L0752: 2, L0599: 2, H0170: 1, H0402: 1, S0444: 1, S0360: 1, H0747: 1, L2486: 1, L3503: 1, H0427: 1, H0644: 1, H0038: 1, L0800: 1, L0648: 1, L0804: 1, H0670: 1, H0478: 1, L0731: 1, L0758: 1, H0445: 1, S0434: 1, L0591: 1 and L0362: 1. 119 HMDAB29 584789 129 AR313: 127, AR039: 86, AR299: 64, AR089: 56, AR185: 51, AR096: 50, AR277: 50, AR300: 42, AR316: 37, AR240: 33, AR218: 27, AR219: 25, AR104: 22, AR060: 22, AR282: 20, AR055: 16, AR283: 9, H0346: 1, H0598: 1 and S0330: 1. 120 HMDAD44 566854 130 AR277: 44, AR283: 35, AR219: 28, AR316: 26, AR089: 24, AR218: 23, AR313: 22, AR282: 22, AR055: 22, AR104: 21, AR299: 20, AR185: 19, AR240: 19, AR096: 17, AR039: 16, AR060: 14, AR300: 14, L0749: 3, H0346: 1, H0370: 1, H0427: 1 and L0439: 1 121 HMEDE24 837027 131 AR219: 112, AR218: 102, AR268: 66, AR299: 42, AR210: 37, AR173: 37, AR269: 36, AR270: 33, AR039: 33, AR290: 29, AR275: 28, AR300: 28, AR096: 28, AR188: 27, AR183: 26, AR175: 25, AR053: 25, AR191: 25, AR189: 25, AR198: 23, AR267: 23, AR211: 23, AR196: 22, AR192: 22, AR162: 22, AR174: 22, AR163: 21, AR161: 21, AR180: 21, AR313: 21, AR274: 20, AR165: 20, AR231: 20, AR271: 20, AR243: 20, AR181: 20, AR247: 20, AR182: 19, AR164: 19, AR089: 19, AR166: 19, AR178: 19, AR199: 18, AR200: 18, AR282: 18, AR238: 18, AR213: 18, AR242: 18, AR240: 17, AR177: 17, AR205: 17, AR195: 17, AR316: 16, AR309: 16, AR246: 16, AR203: 16, AR190: 16, AR212: 15, AR176: 15, AR197: 15, AR308: 15, AR312: 15, AR234: 15, AR272: 14, AR311: 14, AR201: 14, AR245: 14, AR193: 14, AR207: 13, AR179: 13, AR264: 13, AR296: 13, AR185: 13, AR226: 13, AR239: 13, AR263: 13, AR291: 13, AR254: 12, AR233: 12, AR257: 12, AR258: 12, AR255: 12, AR262: 12, AR060: 12, AR285: 12, AR256: 12, AR229: 11, AR232: 11, AR261: 11, AR230: 11, AR293: 11, AR266: 11, AR237: 11, AR236: 11, AR104: 10, AR289: 10, AR253: 9, AR297: 9, AR288: 9, AR287: 9, AR277: 9, AR252: 9, AR260: 9, AR250: 9, AR061: 8, AR204: 8, AR294: 8, AR295: 8, AR283: 8, AR228: 8, AR227: 8, AR033: 7, AR286: 7, AR171: 7, AR235: 7, AR215: 7, AR225: 7, AR170: 6, AR223: 6, AR217: 6, AR221: 5, AR055: 5, AR216: 5, AR169: 5, AR214: 4, AR172: 4, AR168: 4, AR222: 4, AR224: 4, H0266: 1 122 HMEDI90 840077 132 AR104: 7, AR316: 6, AR055: 5, AR060: 5, AR300: 4, AR185: 4, AR218: 4, AR282: 3, AR283: 3, AR240: 3, AR089: 3, AR219: 2, AR299: 2, AR039: 1, AR313: 1, AR096: 1, AR277: 1, L0439: 8, S6028: 2, H0266: 2, L0438: 2, L0745: 2, L0717: 1, S0222: 1, H0052: 1, H0194: 1, H0009: 1, T0010: 1, S0036: 1, L0776: 1, L0789: 1, S0028: 1, L0756: 1 and L0779: 1. 123 HMIBD93 634227 133 AR277: 111, AR283: 78, AR219: 72, AR316: 65, AR104: 61, AR055: 58, AR089: 55, AR218: 54, AR313: 49, AR282: 48, AR299: 47, AR039: 44, AR185: 41, AR096: 39, AR240: 36, AR060: 33, AR300: 31, L0439: 6, L0751: 5, L0770: 3, L0769: 3, L0764: 3, H0617: 2, L0766: 2, L0752: 2, H0445: 2, S6024: 1, H0351: 1, S0222: 1, H0586: 1, S0010: 1, S6028: 1, L0768: 1, L0794: 1, L0438: 1, L0747: 1, L0753: 1 and L0758: 1. 124 HMIBF07 603528 134 AR055: 5, AR060: 4, AR240: 4, AR300: 3, AR299: 3, AR104: 3, AR283: 3, AR219: 2, AR218: 2, AR185: 2, AR039: 2, AR089: 2, AR277: 2, AR096: 2, AR316: 2, AR282: 1, AR313: 1, S6028: 1 125 HMJAK70 610099 135 AR251: 4, AR052: 3, AR263: 3, AR269: 3, AR265: 2, AR282: 2, AR253: 2, AR309: 2, AR238: 2, AR271: 2, AR186: 2, AR247: 2, AR270: 2, AR266: 1, AR277: 1, AR312: 1, AR053: 1, AR295: 1, AR241: 1, AR237: 1, AR310: 1, AR213: 1, AR182: 1, AR175: 1, AR313: 1, AR268: 1, AR226: 1, AR096: 1, H0391: 1 126 HMQAI38 589964 136 AR277: 1, L0794: 3, H0634: 2, H0220: 1, S0476: 1, H0250: 1 and H0635: 1. 127 HMSHY25 886183 137 AR055: 5, AR060: 4, AR282: 4, AR104: 3, AR283: 3, AR300: 3, AR185: 3, AR277: 2, AR039: 2, AR316: 2, AR096: 2, AR089: 2, AR299: 2, AR218: 2, AR219: 2, AR240: 1, S0002: 1 and S0426: 1. 128 HMUAN45 833072 138 AR236: 442, AR228: 429, AR211: 336, AR230: 331, AR287: 325, AR191: 311, AR239: 297, AR174: 289, AR233: 252, AR232: 252, AR190: 238, AR288: 237, AR176: 228, AR203: 222, AR262: 218, AR260: 210, AR199: 209, AR181: 193, AR173: 191, AR163: 186, AR178: 181, AR200: 175, AR162: 165, AR189: 164, AR297: 164, AR166: 154, AR161: 154, AR164: 149, AR188: 148, AR227: 147, AR234: 145, AR261: 144, AR311: 142, AR257: 141, AR210: 140, AR179: 139, AR165: 137, AR272: 136, AR295: 134, AR226: 134, AR255: 130, AR231: 129, AR180: 129, AR285: 127, AR196: 127, AR308: 126, AR275: 123, AR286: 123, AR177: 118, AR238: 117, AR258: 116, AR235: 114, AR237: 104, AR294: 100, AR175: 99, AR264: 98, AR182: 96, AR212: 96, AR293: 93, AR185: 92, AR291: 90, AR267: 79, AR229: 78, AR061: 75, AR240: 74, AR060: 74, AR256: 73, AR269: 65, AR104: 64, AR247: 63, AR274: 60, AR201: 60, AR300: 59, AR033: 56, AR263: 53, AR289: 51, AR183: 49, AR193: 48, AR290: 43, AR195: 41, AR316: 40, AR270: 40, AR296: 37, AR282: 36, AR312: 34, AR197: 33, AR218: 33, AR277: 29, AR299: 29, AR055: 28, AR089: 28, AR250: 27, AR268: 27, AR207: 26, AR309: 25, AR053: 25, AR252: 24, AR266: 21, AR213: 20, AR242: 19, AR224: 19, AR219: 19, AR313: 18, AR223: 18, AR169: 18, AR222: 17, AR171: 17, AR168: 16, AR172: 16, AR205: 15, AR217: 14, AR096: 14, AR245: 14, AR214: 14, AR204: 12, AR225: 12, AR170: 11, AR246: 11, AR254: 11, AR198: 11, AR283: 10, AR192: 10, AR216: 10, AR271: 9, AR253: 9, AR215: 8, AR221: 7, AR039: 5, AR243: 4, AR184: 1, AR310: 1, H0271: 5, H0083: 3, L0794: 3, H0656: 2, H0457: 2, H0179: 2, L0791: 2, H0521: 2, L0744: 2, H0707: 2, H0265: 1, H0556: 1, H0657: 1, H0449: 1, H0580: 1, S0046: 1, H0411: 1, H0437: 1, H0333: 1, H0486: 1, H0250: 1, S6028: 1, H0615: 1, H0628: 1, L0055: 1, H0040: 1, H0634: 1, S0144: 1, H0529: 1, L0769: 1, L0768: 1, L0766: 1, L0803: 1, L0653: 1, L0793: 1, L0666: 1, S0052: 1, H0689: 1, H0522: 1, H0436: 1, L0743: 1, L0749: 1, L0779: 1, H0445: 1 and H0542: 1. 129 HMVBC31 825598 139 AR055: 5, AR316: 4, AR218: 3, AR282: 3, AR104: 2, AR283: 2, AR185: 2, AR096: 2, AR313: 2, AR240: 2, AR060: 2, AR300: 2, AR299: 1, AR277: 1, AR089: 1, AR039: 1, L0748: 10, H0556: 5, S0442: 5, L0438: 4, L0439: 4, L0754: 4, H0050: 3, H0040: 3, L0769: 3, L0806: 3, L0757: 3, L0759: 3, L0601: 3, T0002: 2, S0418: 2, S0358: 2, S0360: 2, H0580: 2, S0476: 2, H0549: 2, H0644: 2, H0529: 2, L0773: 2, L0768: 2, L0766: 2, L0805: 2, L0776: 2, L0663: 2, L0740: 2, L0747: 2, L0749: 2, S0436: 2, H0717: 1, S0212: 1, H0484: 1, H0661: 1, S0376: 1, H0729: 1, H0733: 1, S0007: 1, H0643: 1, L0622: 1, L3653: 1, H0013: 1, H0042: 1, H0052: 1, L0157: 1, L0471: 1, H0373: 1, H0083: 1, H0266: 1, T0006: 1, H0090: 1, H0268: 1, H0494: 1, H0509: 1, H0633: 1, H0646: 1, S0422: 1, S0002: 1, L0761: 1, L0772: 1, L0643: 1, L0644: 1, L0794: 1, L0803: 1, L0555: 1, L0659: 1, L0783: 1, L0809: 1, L5622: 1, H0690: 1, H0658: 1, S0328: 1, S0330: 1, S0152: 1, H0521: 1, H0696: 1, S0044: 1, S0027: 1, L0780: 1, L0752: 1, L0753: 1, L0755: 1, S0434: 1, L0485: 1, H0667: 1, S0276: 1 and S0456: 1. 130 HMWBL03 822861 140 AR313: 27, AR299: 16, AR219: 16, AR218: 14, AR316: 12, AR300: 6, AR039: 5, AR089: 5, AR055: 5, AR060: 4, AR240: 4, AR096: 4, AR282: 4, AR283: 3, AR277: 3, AR185: 3, AR104: 2, S0422: 18, L0766: 7, H0341: 5, S0356: 5, H0543: 5, H0591: 4, H0656: 3, S0354: 3, H0013: 3, T0042: 3, H0659: 3, L0748: 3, L0750: 3, L0777: 3, S0418: 2, S0442: 2, S0444: 2, S0410: 2, L0471: 2, H0040: 2, H0063: 2, H0494: 2, L0646: 2, L0626: 2, L0806: 2, L0655: 2, L0663: 2, S0374: 2, H0547: 2, S0206: 2, L0756: 2, S0436: 2, L0588: 2, H0624: 1, H0171: 1, S0342: 1, H0650: 1, S0360: 1, T0008: 1, H0733: 1, S0046: 1, H0257: 1, H0263: 1, L0738: 1, H0046: 1, L0157: 1, H0039: 1, H0068: 1, H0135: 1, H0090: 1, T0041: 1, H0560: 1, S0440: 1, H0529: 1, L0640: 1, L0771: 1, L0768: 1, L0634: 1, L0529: 1, L5623: 1, L0666: 1, L0665: 1, H0520: 1, H0519: 1, S0328: 1, S0152: 1, S0406: 1, L0751: 1, L0747: 1, L0759: 1, L0591: 1, L0608: 1, H0542: 1, H0423: 1 and H0721: 1. 131 HMWCG28 847413 141 L0439: 19, L0740: 16, L0748: 15, L0766: 12, H0052: 7, L0761: 7, L0741: 7, L0747: 7, H0135: 6, L0769: 6, L0438: 6, S0036: 4, L0770: 4, L0806: 4, L0752: 4, L0731: 4, H0327: 3, H0012: 3, T0010: 3, L0794: 3, L0803: 3, L0783: 3, L0809: 3, L0744: 3, L0758: 3, L0601: 3, H0341: 2, H0550: 2, H0333: 2, L0622: 2, H0599: 2, H0618: 2, H0318: 2, H0051: 2, S0388: 2, S0051: 2, H0100: 2, L0772: 2, L0774: 2, L0664: 2, S0380: 2, L0751: 2, L0745: 2, L0779: 2, L0777: 2, L0753: 2, L0485: 2, H0265: 1, H0381: 1, H0483: 1, S0418: 1, S0354: 1, S0444: 1, S0360: 1, S0046: 1, S0278: 1, H0261: 1, H0455: 1, H0438: 1, H0574: 1, H0559: 1, L0623: 1, H0706: 1, T0048: 1, H0581: 1, H0251: 1, H0597: 1, H0544: 1, H0046: 1, H0457: 1, H0009: 1, H0081: 1, H0620: 1, H0200: 1, H0095: 1, H0275: 1, H0083: 1, H0354: 1, H0266: 1, H0328: 1, H0428: 1, H0070: 1, T0023: 1, H0673: 1, H0124: 1, H0038: 1, H0087: 1, L0351: 1, L0564: 1, H0560: 1, H0130: 1, S0344: 1, L0369: 1, L0763: 1, L0637: 1, L5575: 1, L5565: 1, L3905: 1, L0667: 1, L0641: 1, L0645: 1, L0764: 1, L0775: 1, L0376: 1, L0776: 1, L0606: 1, L0659: 1, L0789: 1, L0666: 1, L0663: 1, L0665: 1, H0693: 1, H0547: 1, H0660: 1, H0539: 1, S0044: 1, H0436: 1, L0742: 1, L0749: 1, L0755: 1, L0759: 1, S0031: 1, S0260: 1, H0445: 1, H0707: 1, S0434: 1, L0581: 1, L0593: 1, S0194: 1, H0543: 1, H0423: 1 and H0506: 1. 132 HNECW49 639117 142 AR055: 8, AR060: 7, AR240: 6, AR185: 5, AR300: 5, AR218: 5, AR104: 5, AR283: 5, AR089: 4, AR299: 4, AR282: 4, AR316: 3, AR039: 3, AR313: 3, AR096: 3, AR277: 2, AR219: 2, H0179: 2 and H0402: 1. 133 HNFCY57 877653 143 H0271: 3, H0575: 2, H0416: 2, H0518: 2, L0748: 2, S6022: 1, L0021: 1, H0024: 1, H0179: 1, S0002: 1, L0794: 1, S0053: 1 and S0216: 1. 134 HNFGR08 825417 144 AR055: 5, AR060: 4, AR185: 3, AR240: 3, AR300: 2, AR104: 2, AR282: 2, AR089: 2, AR283: 2, AR219: 2, AR218: 2, AR316: 1, AR039: 1, AR096: 1, H0271: 1 135 HNGAK51 603910 145 AR313: 60, AR039: 47, AR299: 29, AR277: 29, AR089: 26, AR185: 24, AR096: 23, AR240: 20, AR300: 19, AR316: 17, AR218: 14, AR060: 14, AR219: 14, AR104: 14, AR055: 11, AR282: 10, AR283: 6, S0052: 1 136 HNGDX18 1145071 146 AR228: 8, AR176: 7, AR161: 6, AR162: 6, AR163: 6, AR251: 5, AR223: 5, AR181: 5, AR171: 5, AR225: 4, AR060: 4, AR267: 4; AR055: 4, AR216: 4, AR261: 4, AR235: 4, AR236: 4, AR268: 4, AR230: 4, AR269: 4, AR288: 4, AR191: 4, AR052: 4, AR182: 4, AR221: 4, AR239: 4, AR254: 3, AR242: 3, AR255: 3, AR312: 3, AR233: 3, AR287: 3, AR272: 3, AR262: 3, AR165: 3, AR271: 3, AR244: 3, AR178: 3, AR229: 3, AR164: 3, AR173: 3, AR257: 3, AR290: 3, AR274: 3, AR266: 3, AR061: 3, AR297: 3, AR166: 3, AR282: 3, AR198: 3, AR053: 3, AR231: 3, AR199: 3, AR291: 3, AR177: 3, AR201: 3, AR214: 3, AR264: 3, AR247: 3, AR196: 3, AR224: 3, AR190: 3, AR174: 3, AR270: 3, AR296: 2, AR286: 2, AR300: 2, AR309: 2, AR203: 2, AR089: 2, AR200: 2, AR294: 2, AR289: 2, AR249: 2, AR311: 2, AR240: 2, AR168: 2, AR293: 2, AR238: 2, AR188: 2, AR217: 2, AR175: 2, AR285: 2, AR179: 2, AR234: 2, AR310: 2, AR185: 2, AR033: 2, AR298: 2, AR260: 2, AR226: 2, AR316: 2, AR227: 2, AR222: 2, AR313: 2, AR265: 2, AR197: 2, AR277: 2, AR237: 2, AR189: 2, AR295: 2, AR299: 2, AR193: 2, AR283: 2, AR172: 2, AR183: 2, AR275: 2, AR232: 2, AR211: 2, AR253: 2, AR210: 2, AR104: 2, AR096: 2, AR213: 1, AR258: 1, AR292: 1, AR308: 1, AR273: 1, AR194: 1, AR180: 1, AR184: 1, AR284: 1, AR252: 1, AR205: 1, H0457: 4, S0052: 4, H0271: 3, L0766: 3, H0543: 3, H0255: 2, H0402: 2, H0253: 2, L0805: 2, L0754: 2, H0422: 2, H0583: 1, H0650: 1, H0656: 1, H0484: 1, H0483: 1, H0254: 1, L3659: 1, S0442: 1, S0360: 1, H0580: 1, S0140: 1, H0747: 1, H0393: 1, H0486: 1, H0250: 1, H0618: 1, H0050: 1, H0630: 1, H0719: 1, H0182: 1, H0063: 1, H0087: 1, H0264: 1, H0488: 1, H0487: 1, L0351: 1, T0042: 1, S0448: 1, S0002: 1, L0761: 1, L0378: 1, L0655: 1, L4501: 1, H0539: 1, S0188: 1, S0146: 1, H0707: 1, L0599: 1, H0136: 1, H0423: 1 and H0677: 1. HNGDX18 866177 258 137 HNGFR54 695748 147 S0052: 2 138 HNGGA68 638116 148 AR055: 6, AR060: 6, AR218: 6, AR300: 4, AR185: 4, AR240: 4, AR299: 3, AR104: 3, AR219: 3, AR089: 3, AR282: 3, AR283: 3, AR316: 3, AR096: 2, AR039: 2, AR313: 2, AR277: 2, H0419: 1, H0305: 1 and S0052: 1. 139 HNGHK37 609889 149 AR055: 5, AR060: 5, AR218: 4, AR300: 3, AR185: 3, AR283: 2, AR299: 2, AR240: 2, AR089: 2, AR282: 2, AR104: 2, AR316: 2, AR096: 1, AR313: 1, AR277: 1, AR039: 1, S0052: 1 140 HNGIV64 561572 150 AR185: 8, AR039: 8, AR060: 8, AR313: 7, AR055: 7, AR096: 6, AR300: 6, AR089: 6, AR240: 6, AR218: 6, AR299: 6, AR277: 6, AR316: 5, AR104: 5, AR283: 4, AR282: 3, AR219: 1, S0052: 1 141 HNGJB41 852178 151 AR055: 6, AR060: 6, AR282: 5, AR300: 4, AR277: 4, AR104: 4, AR316: 4, AR283: 4, AR218: 4, AR185: 3, AR299: 3, AR219: 3, AR089: 3, AR313: 3, AR240: 3, AR096: 2, AR039: 2, S0052: 1 142 HNGKT41 836061 152 AR316: 11, AR055: 6, AR060: 6, AR277: 5, AR300: 5, AR282: 5, AR104: 4, AR240: 4, AR185: 4, AR218: 3, AR283: 3, AR313: 3, AR039: 3, AR089: 3, AR219: 3, AR096: 2, AR299: 2, S0428: 1 143 HNGMW45 838613 153 AR316: 3, S0428: 1 144 HNGNO53 836063 154 AR055: 7, AR060: 6, AR240: 5, AR300: 5, AR218: 5, AR185: 4, AR283: 4, AR299: 4, AR277: 4, AR089: 4, AR104: 3, AR316: 3, AR096: 3, AR219: 2, AR313: 2, AR039: 2, AR282: 1, S0428: 2 and L0439: 1. 145 HNGPJ25 834942 155 AR060: 7, AR055: 7, AR218: 6, AR240: 6, AR282: 5, AR185: 5, AR277: 5, AR300: 5, AR299: 4, AR283: 3, AR089: 3, AR104: 3, AR316: 3, AR096: 3, AR039: 2, AR313: 2, AR219: 2, H0251: 8, H0624: 4, L0752: 4, H0286: 1, L0598: 1, S0428: 1 and H0144: 1. 146 HNHCT47 634691 156 AR313: 39, AR039: 38, AR219: 29, AR218: 24, AR299: 23, AR185: 22, AR096: 21, AR089: 20, AR300: 17, AR316: 15, AR060: 14, AR277: 14, AR104: 13, AR055: 12, AR240: 11, AR282: 10, AR283: 8, S0053: 2 and S0046: 1. 147 HNHKI74 777856 157 S0216: 1 148 HNHKV56 800877 158 S0216: 1 and L0746: 1. 149 HOACG07 792928 159 AR202: 138, AR194: 120, AR315: 99, AR281: 99, AR198: 98, AR244: 88, AR246: 86, AR243: 85, AR205: 85, AR192: 82, AR241: 80, AR280: 79, AR204: 73, AR265: 70, AR283: 66, AR206: 63, AR310: 59, AR263: 57, AR271: 57, AR314: 56, AR273: 54, AR053: 50, AR052: 49, AR282: 49, AR033: 48, AR277: 47, AR275: 46, AR213: 45, AR274: 44, AR312: 43, AR316: 43, AR309: 42, AR104: 40, AR240: 40, AR300: 40, AR289: 39, AR096: 39, AR266: 38, AR251: 37, AR247: 36, AR089: 36, AR299: 36, AR284: 35, AR313: 35, AR186: 34, AR039: 33, AR055: 33, AR175: 32, AR219: 31, AR295: 31, AR291: 29, AR177: 28, AR218: 28, AR185: 27, AR268: 26, AR285: 26, AR270: 25, AR286: 25, AR253: 24, AR183: 24, AR060: 24, AR232: 23, AR061: 23, AR292: 23, AR298: 23, AR258: 22, AR256: 20, AR248: 20, AR296: 19, AR182: 19, AR238: 18, AR269: 18, AR290: 18, AR294: 18, AR267: 17, AR231: 17, AR226: 17, AR259: 17, AR229: 16, AR227: 16, AR234: 16, AR293: 15, AR233: 15, AR237: 14, AR249: 13, AR184: 13, AR179: 11 L0748: 4, L0749: 4, H0265: 3, S0442: 2, H0587: 2, H0427: 2, S0142: 2, L0769: 2, L0761: 2, L0800: 2, L0794: 2, L0657: 2, L0659: 2, L0663: 2, L0665: 2, H0689: 2, L0731: 2, H0677: 2, H0713: 1, H0716: 1, H0657: 1, H0661: 1, H0638: 1, S0360: 1, H0722: 1, H0122: 1, H0545: 1, H0009: 1, H0123: 1, S0388: 1, H0252: 1, T0023: 1, T0006: 1, H0135: 1, H0163: 1, H0412: 1, L0351: 1, S0440: 1, H0529: 1, L0372: 1, L0646: 1, L0645: 1, L0764: 1, L0662: 1, L0767: 1, L0766: 1, L0649: 1, L0803: 1, L0776: 1, L0655: 1, L0382: 1, L0809: 1, L0789: 1, H0672: 1, H0627: 1, L0751: 1, L0750: 1, L0753: 1, L0757: 1, L0758: 1 and L0759: 1. 150 HODBB70 520196 160 AR055: 7, AR218: 6, AR060: 5, AR104: 5, AR240: 4, AR300: 4, AR299: 4, AR096: 4, AR219: 4, AR283: 4, AR039: 3, AR185: 3, AR089: 3, AR316: 3, AR282: 3, AR277: 2, H0328: 1, L0789: 1, L0742: 1 and L0439: 1. 151 HOEBK60 789396 161 AR219: 21, AR218: 19, AR316: 12, AR313: 10, AR039: 9, AR096: 8, AR089: 8, AR299: 7, AR240: 7, AR055: 7, AR300: 7, AR060: 7, AR282: 6, AR185: 5, AR283: 5, AR104: 4, AR277: 4, L0439: 10, L0731: 7, L0605: 6, L0766: 5, L0803: 5, L0471: 4, L0655: 4, L0659: 4, L0756: 4, S0408: 3, S0440: 3, H0648: 3, L0777: 3, H0170: 2, S0420: 2, L0021: 2, H0014: 2, T0010: 2, L0143: 2, H0090: 2, H0591: 2, H0641: 2, L0638: 2, L0662: 2, L0794: 2, L0776: 2, L0657: 2, L0809: 2, L0666: 2, L0663: 2, H0547: 2, S0126: 2, H0518: 2, L0751: 2, L0755: 2, L0758: 2, L0588: 2, H0543: 2, H0624: 1, H0740: 1, S0430: 1, H0657: 1, H0656: 1, S0212: 1, S0110: 1, H0661: 1, H0663: 1, S0442: 1, S0358: 1, S0376: 1, S0360: 1, S0476: 1, L0717: 1, L0586: 1, T0114: 1, H0427: 1, L0105: 1, H0318: 1, S0474: 1, H0581: 1, H0052: 1, H0309: 1, L0157: 1, H0024: 1, H0071: 1, H0275: 1, H0354: 1, S6028: 1, H0266: 1, S0003: 1, H0328: 1, H0615: 1, H0428: 1, H0031: 1, H0169: 1, H0163: 1, H0038: 1, H0040: 1, H0551: 1, H0272: 1, T0041: 1, S0014: 1, S0438: 1, H0646: 1, S0142: 1, S0210: 1, S0426: 1, H0529: 1, L0372: 1, L0645: 1, L0764: 1, L0651: 1, L0656: 1, L5623: 1, L0789: 1, L0665: 1, H0520: 1, H0689: 1, H0682: 1, H0435: 1, H0659: 1, S0380: 1, H0696: 1, L0740: 1, L0754: 1, L0746: 1, L0750: 1, L0779: 1, L0752: 1, S0260: 1, S0434: 1, S0436: 1, L0485: 1 and H0423: 1. 152 HOFMO16 596835 162 AR281: 9, AR263: 7, AR265: 7, AR277: 7, AR183: 6, AR283: 6, AR204: 6, AR251: 6, AR243: 5, AR315: 5, AR282: 5, AR267: 4, AR182: 4, AR240: 4, AR316: 4, AR269: 4, AR280: 4, AR247: 4, AR310: 4, AR299: 4, AR234: 4, AR300: 4, AR238: 4, AR060: 4, AR096: 4, AR266: 4, AR268: 4, AR294: 4, AR055: 4, AR309: 4, AR184: 4, AR313: 3, AR270: 3, AR253: 3, AR312: 3, AR289: 3, AR275: 3, AR033: 3, AR104: 3, AR292: 3, AR229: 3, AR226: 3, AR206: 3, AR053: 3, AR231: 3, AR284: 3, AR219: 3, AR202: 3, AR205: 3, AR218: 3, AR295: 3, AR039: 3, AR089: 3, AR052: 3, AR232: 3, AR061: 3, AR296: 3, AR185: 3, AR186: 3, AR227: 3, AR286: 3, AR285: 3, AR291: 3, AR246: 3, AR290: 3, AR233: 2, AR293: 2, AR271: 2, AR198: 2, AR237: 2, AR298: 2, AR213: 2, AR175: 2, AR177: 2, AR256: 2, AR273: 2, AR258: 2, AR241: 1, AR314: 1, AR259: 1, AR248: 1, AR192: 1, H0415: 1 153 HOFNB74 762821 163 AR277: 18, AR283: 18, AR282: 14, AR313: 12, AR316: 11, AR055: 9, AR089: 9, AR240: 8, AR104: 8, AR218: 8, AR299: 8, AR096: 8, AR219: 8, AR300: 7, AR185: 7, AR039: 6, AR060: 5, H0415: 1 154 HOHBO66 853375 164 L0766: 6, L0747: 5, S0408: 4, L0748: 4, L0663: 3, L0758: 3, H0556: 2, H0637: 2, H0486: 2, H0581: 2, H0052: 2, H0530: 2, H0560: 2, H0641: 2, L0764: 2, L0783: 2, S0328: 2, L0751: 2, L0592: 2, H0543: 2, H0422: 2, H0650: 1, H0656: 1, H0663: 1, H0638: 1, S0418: 1, S0420: 1, S0356: 1, S0376: 1, S0132: 1, S6026: 1, S0278: 1, S0222: 1, H0586: 1, H0632: 1, H0069: 1, H0427: 1, T0082: 1, H0457: 1, H0083: 1, H0510: 1, H0188: 1, L0138: 1, S0250: 1, H0644: 1, L0143: 1, H0068: 1, H0551: 1, T0041: 1, L0769: 1, L0761: 1, L0800: 1, L0644: 1, L0767: 1, L0768: 1, L0655: 1, L0659: 1, L0368: 1, H0144: 1, H0702: 1, H0547: 1, H0519: 1, H0711: 1, H0690: 1, H0435: 1, H0670: 1, S3012: 1, L0755: 1, L0731: 1, S0031: 1, L0596: 1, H0653: 1 and H0506: 1. 155 HORBS82 638293 165 H0706: 2, L0809: 2, S0360: 1, L0623: 1, H0122: 1, H0041: 1, H0095: 1, H0292: 1, H0424: 1, S0364: 1, L0794: 1, L0787: 1, L0663: 1, H0780: 1, H0435: 1, L0743: 1, L0747: 1 and L0731: 1. 156 HORBV76 839270 166 AR313: 8, AR218: 8, AR060: 7, AR055: 7, AR219: 6, AR240: 6, AR185: 6, AR282: 5, AR299: 5, AR039: 5, AR316: 5, AR089: 5, AR300: 4, AR096: 4, AR283: 4, AR104: 4, AR277: 3, L0794: 2, L0608: 2, H0686: 1, S0278: 1, H0292: 1, H0031: 1, L0065: 1, S0344: 1, L0638: 1, L0662: 1, L0803: 1, L0659: 1, L0665: 1, L0749: 1 and L0780: 1. 157 HOSDO75 862049 167 AR060: 6, AR055: 6, AR218: 6, AR240: 5, AR277: 5, AR300: 4, AR185: 4, AR299: 4, AR283: 4, AR089: 4, AR282: 3, AR104: 3, AR316: 3, AR096: 3, AR313: 2, AR039: 2, AR219: 2, L0766: 2, L0362: 2, S0358: 1, H0580: 1, S0046: 1, H0266: 1, S0003: 1, H0553: 1, S0344: 1, L0761: 1, L0794: 1, S0152: 1, L0777: 1 and L0755: 1. 158 HOSEI81 562778 168 AR055: 5, AR060: 5, AR104: 4, AR282: 4, AR300: 4, AR299: 3, AR185: 3, AR089: 3, AR240: 3, AR039: 3, AR283: 2, AR218: 2, AR096: 2, AR316: 2, AR219: 2, AR313: 2, AR277: 2, L0777: 2, S0214: 1 and H0539: 1. 159 HOUDE92 580866 169 H0052: 17, L0745: 11, L0748: 10, H0547: 7, L0439: 7, L0755: 6, L0771: 5, L0774: 5, L0662: 4, L0746: 4, L0777: 4, S0474: 3, L0163: 3, H0059: 3, H0100: 3, L0775: 3, L0741: 3, H0261: 2, H0333: 2, H0194: 2, H0545: 2, H0012: 2, H0617: 2, H0135: 2, L0770: 2, L0665: 2, L0438: 2, H0520: 2, L0747: 2, L0752: 2, L0753: 2, S0040: 1, L0717: 1, H0437: 1, H0550: 1, S6016: 1, H0497: 1, H0574: 1, H0599: 1, H0575: 1, H0618: 1, H0253: 1, H0041: 1, H0620: 1, H0373: 1, H0188: 1, H0124: 1, H0068: 1, H0040: 1, H0561: 1, S0448: 1, S0210: 1, L0763: 1, L0644: 1, L0767: 1, L0768: 1, L0375: 1, L0651: 1, L0659: 1, L0540: 1, L5622: 1, H0144: 1, H0593: 1, S0126: 1, H0539: 1, S0152: 1, H0694: 1, S0390: 1, S0028: 1, L0749: 1, L0786: 1, L0780: 1, L0731: 1, L0757: 1, L0758: 1, S0436: 1, L0592: 1 and S0276: 1. 160 HPCAL26 762822 170 L0659: 11, S0126: 11, L0731: 11, S0192: 11, L0666: 9, L0777: 7, T0049: 5, S0358: 5, L0771: 5, L0757: 5, S0360: 4, S0440: 4, L0740: 4, L0758: 4, S0212: 3, S0356: 3, S0046: 3, H0369: 3, H0545: 3, L0662: 3, L0774: 3, L0809: 3, H0519: 3, L0752: 3, S0011: 3, H0295: 2, H0662: 2, S0468: 2, H0012: 2, H0024: 2, H0356: 2, H0616: 2, H0268: 2, H0412: 2, L0646: 2, L0803: 2, S0013: 2, L0754: 2, L0747: 2, L0759: 2, S0040: 1, S0418: 1, S0442: 1, S0376: 1, H0676: 1, L0717: 1, H0550: 1, S0222: 1, H0574: 1, L0021: 1, H0575: 1, H0036: 1, H0590: 1, H0618: 1, T0048: 1, H0309: 1, H0596: 1, T0110: 1, H0546: 1, H0046: 1, H0123: 1, H0014: 1, S0003: 1, S0022: 1, H0428: 1, H0622: 1, H0031: 1, H0673: 1, L0455: 1, H0316: 1, H0598: 1, H0163: 1, H0038: 1, H0433: 1, H0413: 1, T0069: 1, S0438: 1, H0633: 1, H0647: 1, S0210: 1, L0770: 1, L0769: 1, L0768: 1, L0794: 1, L0519: 1, L0789: 1, L0790: 1, L0664: 1, L0665: 1, H0144: 1, S0330: 1, S0136: 1, H0696: 1, S3014: 1, S0206: 1, L0751: 1, L0749: 1, L0756: 1, L0779: 1, S0031: 1, S0242: 1, S0194: 1 and S0276: 1. 161 HPEAD23 773409 171 AR277: 68, AR283: 65, AR219: 61, AR316: 49, AR218: 41, AR089: 41, AR104: 39, AR299: 38, AR055: 36, AR185: 36, AR039: 34, AR282: 33, AR240: 31, AR096: 31, AR313: 31, AR060: 30, AR300: 25, H0585: 18, L0779: 3, L0775: 2, S0374: 2, H0341: 1, S0358: 1, S0360: 1, S0408: 1, H0559: 1, T0039: 1, H0156: 1, H0253: 1, S0182: 1, H0318: 1, H0545: 1, H0083: 1, H0165: 1, L0768: 1, L0774: 1, L0750: 1, L0752: 1 and S0031: 1. 162 HPEBA84 753957 172 AR313: 5, AR240: 4, AR299: 4, AR185: 4, AR300: 4, AR060: 4, AR055: 3, AR089: 3, AR096: 2, AR282: 2, AR039: 2, AR218: 2, AR316: 2, AR277: 1, AR219: 1, AR104: 1, L0591: 2, L3643: 1, S0420: 1, L3388: 1, H0057: 1, H0166: 1, L0648: 1, L0518: 1, L0809: 1, L0519: 1, L0754: 1 and L0599: 1. 163 HPFCI36 855966 173 AR218: 18, AR219: 16, AR313: 14, AR089: 9, AR055: 7, AR282: 6, AR060: 6, AR316: 6, AR185: 6, AR299: 5, AR240: 5, AR039: 5, AR300: 4, AR104: 4, AR283: 4, AR096: 4, AR277: 2, L0591: 4, L0754: 3, H0450: 2, H0486: 2, H0046: 2, S0003: 2, H0494: 2, S0422: 2, L0659: 2, S0126: 2, H0659: 2, L0750: 2, L0601: 2, H0170: 1, H0556: 1, H0657: 1, S0420: 1, S0354: 1, H0734: 1, H0749: 1, H0455: 1, H0403: 1, H0600: 1, H0013: 1, H0156: 1, H0599: 1, H0744: 1, H0082: 1, S0214: 1, H0622: 1, H0031: 1, H0673: 1, H0169: 1, H0090: 1, H0038: 1, H0022: 1, H0560: 1, L0643: 1, L0771: 1, L0773: 1, L0655: 1, L0807: 1, L3872: 1, L0792: 1, L0665: 1, L3811: 1, S0378: 1, H0518: 1, S0152: 1, H0521: 1, L0748: 1, L0749: 1, L0757: 1, L0759: 1, S0434: 1, L0596: 1, L0605: 1 and H0653: 1. 164 HPFDI37 862056 174 AR055: 5, AR218: 5, AR060: 4, AR299: 3, AR300: 3, AR283: 3, AR104: 3, AR282: 3, AR240: 3, AR039: 2, AR219: 2, AR277: 2, AR185: 2, AR316: 2, AR089: 2, AR313: 2, AR096: 1, L0771: 13, L0752: 12, L0748: 9, L0731: 7, S0360: 6, L0769: 6, S0358: 5, H0318: 5, L0770: 5, L0747: 5, L0758: 5, L0599: 5, H0140: 4, H0545: 4, H0673: 4, L0774: 4, L0655: 4, L0659: 4, L0664: 4, L0665: 4, H0659: 4, H0648: 4, L0740: 4, L0754: 4, L0588: 4, H0662: 3, H0169: 3, H0413: 3, L0638: 3, L0775: 3, L0783: 3, L0666: 3, L0663: 3, H0660: 3, H0521: 3, L0749: 3, L0750: 3, L0757: 3, H0543: 3, H0170: 2, S0110: 2, H0574: 2, H0581: 2, H0535: 2, L0065: 2, H0647: 2, S0344: 2, L0763: 2, L0764: 2, L0662: 2, L0767: 2, L0803: 2, L0806: 2, L0776: 2, S0374: 2, S0328: 2, S0380: 2, H0576: 2, S0028: 2, L0591: 2, H0352: 2, H0265: 1, T0002: 1, H0686: 1, H0685: 1, H0295: 1, H0657: 1, L0760: 1, S0212: 1, H0484: 1, H0177: 1, H0638: 1, L0617: 1, L0005: 1, S0442: 1, S0376: 1, H0637: 1, H0411: 1, H0370: 1, H0587: 1, H0632: 1, T0109: 1, H0156: 1, H0085: 1, H0327: 1, H0530: 1, H0046: 1, H0041: 1, S0388: 1, H0630: 1, H0271: 1, H0644: 1, H0628: 1, H0181: 1, H0617: 1, H0674: 1, H0068: 1, H0040: 1, H0488: 1, L0564: 1, T0041: 1, H0494: 1, H0633: 1, S0144: 1, S0210: 1, S0422: 1, L0369: 1, L0762: 1, L0372: 1, L0646: 1, L0765: 1, L0363: 1, L0768: 1, L0651: 1, L0653: 1, L0629: 1, L0657: 1, L0526: 1, L0532: 1, S0053: 1, S0216: 1, H0144: 1, H0519: 1, S0126: 1, H0689: 1, H0690: 1, H0684: 1, S0027: 1, L0742: 1, L0756: 1, L0780: 1, L0755: 1, H0444: 1, H0445: 1, L0596: 1, L0605: 1, L0592: 1, L0593: 1, L0362: 1, L0603: 1 and H0136: 1. 165 HPIAA80 829972 175 AR218: 13, AR219: 11, AR282: 9, AR089: 8, AR055: 8, AR240: 7, AR104: 6, AR060: 6, AR283: 6, AR277: 6, AR039: 6, AR316: 5, AR299: 5, AR096: 4, AR185: 4, AR300: 4, AR313: 3, L0750: 3, H0672: 2, L0744: 2, H0587: 1, L0021: 1, S0010: 1, H0024: 1, H0266: 1, S0364: 1, H0068: 1, H0038: 1, T0004: 1, H0625: 1, S0150: 1, L0769: 1, L0667: 1, L0649: 1, L0784: 1, L0526: 1, L0790: 1, L0792: 1, L0793: 1, L0663: 1, H0696: 1, L0747: 1, L0608: 1 and S0276: 1. 166 HPJCW58 612866 176 AR055: 8, AR060: 6, AR282: 6, AR218: 5, AR104: 4, AR300: 4, AR240: 4, AR283: 4, AR219: 4, AR299: 3, AR089: 3, AR185: 3, AR316: 3, AR096: 3, AR039: 2, AR277: 2, AR313: 1, S0152: 1 167 HPMCV30 612870 177 L0526: 11, L0622: 8, H0670: 8, H0087: 7, S0360: 5, H0594: 5, H0188: 5, H0412: 5, S0206: 5, H0218: 4, S0418: 4, H0318: 4, H0024: 4, H0617: 4, L0770: 4, L0783: 4, S0328: 4, S0027: 4, H0265: 3, H0663: 3, T0048: 3, H0597: 3, H0123: 3, H0673: 3, S0366: 3, H0135: 3, H0616: 3, S0002: 3, L0775: 3, L0776: 3, L0518: 3, L0663: 3, H0144: 3, S0374: 3, S0126: 3, S0380: 3, S3014: 3, H0352: 3, H0624: 2, H0556: 2, H0219: 2, S0114: 2, H0657: 2, H0341: 2, S0110: 2, H0661: 2, H0305: 2, H0351: 2, H0492: 2, T0039: 2, H0052: 2, H0546: 2, H0178: 2, H0083: 2, H0688: 2, H0068: 2, H0038: 2, H0040: 2, H0509: 2, S0142: 2, S0426: 2, L0769: 2, L0521: 2, L0768: 2, H0689: 2, L0750: 2, H0445: 2, H0170: 1, H0686: 1, H0344: 1, H0295: 1, H0294: 1, S0134: 1, S0218: 1, H0650: 1, L0760: 1, S0116: 1, S0001: 1, H0483: 1, H0255: 1, H0662: 1, H0402: 1, S0358: 1, S0376: 1, H0675: 1, H0580: 1, S0046: 1, S0132: 1, S0278: 1, H0549: 1, H0441: 1, H0370: 1, H0455: 1, H0333: 1, H0643: 1, L0623: 1, T0060: 1, H0250: 1, T0082: 1, S0010: 1, H0505: 1, H0421: 1, H0327: 1, H0545: 1, H0150: 1, H0086: 1, H0012: 1, H0099: 1, H0109: 1, H0290: 1, T0023: 1, H0031: 1, H0181: 1, H0606: 1, H0166: 1, H0674: 1, H0124: 1, H0163: 1, H0063: 1, H0551: 1, H0413: 1, H0102: 1, H0560: 1, S0372: 1, H0130: 1, S0144: 1, S0344: 1, S0422: 1, L0598: 1, L0507: 1, L0639: 1, L0648: 1, L0662: 1, L0767: 1, L0524: 1, L0805: 1, L0659: 1, L0542: 1, L0809: 1, L0530: 1, L0789: 1, H0691: 1, H0520: 1, H0519: 1, H0682: 1, H0684: 1, H0659: 1, H0658: 1, H0648: 1, H0672: 1, S0378: 1, S0152: 1, S0174: 1, H0576: 1, L0612: 1, H0540: 1, L0748: 1, L0740: 1, L0752: 1, L0758: 1, S0436: 1, L0485: 1, L0599: 1, L0608: 1, L0595: 1, L0362: 1, L0366: 1, S0106: 1, H0543: 1, S0446: 1, L0600: 1 and H0008: 1. 168 HPRBH85 695752 178 AR284: 14, AR295: 10, AR271: 8, AR293: 7, AR246: 7, AR243: 7, AR291: 7, AR244: 6, AR286: 6, AR290: 6, AR241: 6, AR285: 6, AR206: 6, AR310: 5, AR249: 5, AR273: 5, AR198: 5, AR280: 5, AR312: 5, AR186: 5, AR270: 5, AR294: 5, AR204: 5, AR269: 5, AR251: 5, AR202: 5, AR292: 5, AR275: 4, AR033: 4, AR253: 4, AR053: 4, AR182: 4, AR314: 4, AR259: 4, AR315: 4, AR298: 4, AR265: 4, AR309: 4, AR282: 4, AR274: 4, AR183: 4, AR061: 4, AR205: 4, AR296: 4, AR289: 4, AR052: 4, AR313: 4, AR175: 3, AR213: 3, AR238: 3, AR268: 3, AR248: 3, AR055: 3, AR177: 3, AR247: 3, AR231: 3, AR104: 3, AR256: 3, AR226: 2, AR185: 2, AR283: 2, AR277: 2, AR267: 2, AR227: 2, AR300: 2, AR096: 2, AR089: 2, AR258: 2, AR219: 2, AR263: 2, AR299: 2, AR237: 2, AR240: 2, AR060: 2, AR316: 2, AR218: 2, AR281: 2, AR039: 2, AR233: 1, AR232: 1, AR184: 1, AR234: 1, AR266: 1, AR192: 1 L0439: 5, L0740: 4, L0777: 4, L0755: 4, L0794: 2, L0803: 2, L0438: 2, L0602: 2, L0752: 2, L0599: 2, H0713: 1, H0583: 1, S0360: 1, L3653: 1, L0471: 1, H0510: 1, H0032: 1, H0488: 1, H0413: 1, L0662: 1, L0804: 1, L0775: 1, L0805: 1, L0655: 1, L0809: 1, L0519: 1, S0148: 1, H0547: 1, L0747: 1, L0686: 1 and H0665: 1. 169 HPRCD35 853551 179 AR104: 14, AR089: 11, AR055: 11, AR185: 10, AR219: 10, AR299: 10, AR218: 10, AR313: 10, AR282: 10, AR240: 9, AR316: 9, AR283: 9, AR096: 8, AR060: 7, AR039: 6, AR300: 5, AR277: 5, L0748: 5, L0754: 5, L0803: 4, L0805: 4, L0777: 4, L0662: 3, L0766: 3, H0556: 2, H0013: 2, H0551: 2, H0264: 2, L0800: 2, L0806: 2, L0664: 2, L0439: 2, L0756: 2, L0758: 2, S0192: 2, H0657: 1, S0442: 1, S0358: 1, S0045: 1, S0046: 1, H0747: 1, H0550: 1, H0392: 1, S0280: 1, H0575: 1, H0545: 1, H0046: 1, H0050: 1, H0644: 1, H0617: 1, L0055: 1, H0032: 1, H0212: 1, H0038: 1, H0560: 1, S0438: 1, S0210: 1, L0769: 1, L0796: 1, L5575: 1, L0768: 1, L0794: 1, L0649: 1, L0776: 1, L0659: 1, L0542: 1, L0526: 1, L0663: 1, H0144: 1, L0565: 1, L3811: 1, H0683: 1, H0659: 1, S0152: 1, H0521: 1, H0522: 1, H0540: 1, S0118: 1, S0032: 1, L0731: 1, L0759: 1 and H0668: 1. 170 HPRCM72 813512 180 AR104: 11, AR219: 9, AR218: 9, AR039: 8, AR055: 6, AR313: 6, AR096: 6, AR240: 6, AR060: 6, AR316: 5, AR300: 4, AR185: 4, AR089: 4, AR299: 4, AR282: 3, AR277: 3, AR283: 3, L0766: 11, L0748: 10, L0731: 6, L0805: 5, L0776: 5, L0777: 5, L0752: 5, L0759: 5, L0659: 4, L0666: 4, L0665: 4, L0754: 4, L0749: 4, L0757: 4, S0358: 3, H0580: 3, H0519: 3, L0740: 3, L0756: 3, H0624: 2, H0716: 2, H0208: 2, H0574: 2, H0052: 2, S0003: 2, H0328: 2, L0649: 2, L0663: 2, L0439: 2, L0745: 2, L0747: 2, S0436: 2, L0605: 2, L0362: 2, H0170: 1, H0686: 1, S0212: 1, H0483: 1, H0255: 1, L3658: 1, S0348: 1, S0418: 1, S0376: 1, S0360: 1, L3646: 1, L3649: 1, S0007: 1, H0619: 1, S0222: 1, H0586: 1, H0486: 1, H0250: 1, S0010: 1, L0105: 1, S0474: 1, H0194: 1, H0327: 1, H0565: 1, H0123: 1, H0050: 1, H0024: 1, H0015: 1, S0051: 1, S0318: 1, S0316: 1, S0214: 1, H0553: 1, H0030: 1, H0032: 1, H0068: 1, H0163: 1, H0413: 1, S0038: 1, S0344: 1, S0422: 1, S0426: 1, L0763: 1, L0761: 1, L0642: 1, L0521: 1, L0662: 1, L0768: 1, L0794: 1, L0803: 1, L0774: 1, L0775: 1, L0376: 1, L0806: 1, L0657: 1, L0517: 1, L0545: 1, L0529: 1, L0791: 1, L0664: 1, H0144: 1, L0438: 1, H0520: 1, H0689: 1, H0684: 1, H0435: 1, H0660: 1, H0672: 1, H0539: 1, H0521: 1, L0750: 1, L0779: 1, L0755: 1, S0031: 1, L0608: 1, S0242: 1, S0276: 1, H0542: 1, H0543: 1, H0423: 1 and H0506: 1. 171 HPTRE80 884167 181 AR277: 53, AR283: 38, AR219: 37, AR316: 30, AR282: 30, AR218: 28, AR089: 28, AR299: 27, AR313: 27, AR104: 26, AR240: 25, AR096: 24, AR185: 24, AR039: 24, AR300: 22, AR055: 21, AR060: 19, L0769: 5, L0759: 4, H0402: 3, S0376: 3, H0424: 3, L0806: 3, L0749: 3, S0222: 2, L0535: 2, L0774: 2, L0384: 2, L0666: 2, H0423: 2, H0265: 1, S0218: 1, H0484: 1, S0354: 1, S0444: 1, S0360: 1, S0007: 1, H0392: 1, H0559: 1, H0486: 1, T0039: 1, T0060: 1, L0021: 1, H0004: 1, H0581: 1, H0052: 1, H0194: 1, H0204: 1, L0471: 1, H0024: 1, H0405: 1, H0617: 1, H0606: 1, H0090: 1, H0272: 1, H0494: 1, S0438: 1, S0422: 1, S0002: 1, L0763: 1, L0770: 1, L0772: 1, L0372: 1, L0646: 1, L0800: 1, L0641: 1, L0645: 1, L0771: 1, L0768: 1, L0794: 1, L0381: 1, L0775: 1, L0789: 1, H0547: 1, H0519: 1, H0659: 1, H0658: 1, H0672: 1, H0521: 1, S0406: 1, H0727: 1, L0744: 1, L0740: 1, L0747: 1, L0779: 1, L0731: 1, L0757: 1, L0758: 1, H0445: 1 and H0422: 1. 172 HPTRI42 655362 182 AR185: 34, AR060: 22, AR299: 19, AR104: 12, AR277: 10, AR282: 10, AR089: 9, AR055: 9, AR316: 8, AR219: 8, AR218: 8, AR096: 8, AR283: 7, AR300: 7, AR240: 7, AR039: 5, AR313: 5, H0036: 3, H0618: 3, L3905: 3, H0619: 2, H0424: 2, L0776: 2, H0136: 2, S0276: 2, H0717: 1, H0716: 1, H0742: 1, S0045: 1, H0261: 1, H0497: 1, H0250: 1, H0575: 1, H0310: 1, H0052: 1, H0123: 1, H0024: 1, S0250: 1, H0401: 1, H0169: 1, H0616: 1, L0351: 1, H0561: 1, S0440: 1, S0150: 1, H0647: 1, H0646: 1, H0652: 1, L0768: 1, L0766: 1, L0803: 1, L0659: 1, L0809: 1, L0666: 1, L0665: 1, S0126: 1, H0672: 1, H0539: 1, S0406: 1, H0576: 1, L0439: 1, L0779: 1, L0777: 1 and H0423: 1. 173 HPTRM02 812879 183 H0617: 7, H0087: 6, H0657: 5, S0410: 3, L0754: 3, S0356: 2, L0717: 2, H0150: 2, H0687: 2, H0424: 2, H0551: 2, L0769: 2, L0774: 2, L0743: 2, L0758: 2, L0592: 2, H0556: 1, T0002: 1, H0686: 1, H0685: 1, T0049: 1, H0663: 1, S0442: 1, S0444: 1, S0360: 1, S0476: 1, H0550: 1, H0486: 1, H0250: 1, L0021: 1, T0048: 1, S0474: 1, S0049: 1, H0052: 1, H0309: 1, H0597: 1, H0544: 1, H0014: 1, H0107: 1, S6028: 1, H0622: 1, H0644: 1, H0102: 1, S0038: 1, L0351: 1, S0450: 1, S0344: 1, S0002: 1, L0764: 1, L0766: 1, L0805: 1, L0776: 1, L0655: 1, L0661: 1, L0657: 1, L0809: 1, L0666: 1, L0665: 1, L2652: 1, L2260: 1, L2261: 1, H0689: 1, H0435: 1, H0521: 1, H0696: 1, H0555: 1, L0744: 1, L0439: 1, L0749: 1, L0777: 1, L0755: 1, L0759: 1, S0436: 1, L0597: 1, L0599: 1, L0366: 1 and S0196: 1. 174 HPTRQ52 655363 184 AR219: 43, AR277: 42, AR104: 34, AR283: 31, AR218: 30, AR316: 28, AR240: 27, AR096: 25, AR089: 24, AR185: 23, AR039: 23, AR313: 21, AR055: 21, AR282: 20, AR299: 20, AR060: 19, AR300: 15, H0694: 12, L0748: 10, L0731: 7, L0754: 6, H0556: 5, L0758: 5, H0265: 4, S0420: 4, S0408: 4, L0517: 4, H0657: 3, H0618: 3, H0052: 3, H0083: 3, H0553: 3, H0494: 3, L0763: 3, L0666: 3, L0663: 3, S0126: 3, L0747: 3, H0295: 2, S0134: 2, S0418: 2, H0637: 2, S0046: 2, H0431: 2, H0545: 2, H0014: 2, H0271: 2, H0039: 2, H0424: 2, H0124: 2, H0641: 2, L0764: 2, L0766: 2, L0774: 2, L0775: 2, L0776: 2, L0655: 2, L0783: 2, L0665: 2, H0519: 2, H0522: 2, S0044: 2, L0755: 2, S0436: 2, L0595: 2, L0362: 2, H0543: 2, S0040: 1, H0740: 1, H0656: 1, S0212: 1, H0484: 1, H0661: 1, H0662: 1, S0360: 1, H0733: 1, H0619: 1, S0222: 1, H0486: 1, H0156: 1, H0575: 1, H0706: 1, H0253: 1, S0010: 1, S0346: 1, H0318: 1, H0596: 1, H0231: 1, H0046: 1, H0150: 1, H0081: 1, H0050: 1, H0012: 1, H0620: 1, L0163: 1, S0051: 1, T0010: 1, S6028: 1, H0266: 1, H0179: 1, H0292: 1, H0031: 1, H0644: 1, H0182: 1, H0617: 1, H0606: 1, H0673: 1, L0455: 1, L0456: 1, H0598: 1, H0038: 1, H0040: 1, H0616: 1, H0087: 1, T0067: 1, H0264: 1, T0041: 1, H0131: 1, H0647: 1, S0002: 1, L0772: 1, L0642: 1, L0662: 1, L0767: 1, L0657: 1, L0659: 1, L0382: 1, L5623: 1, L0664: 1, S0374: 1, H0593: 1, H0690: 1, H0682: 1, H0659: 1, H0658: 1, H0666: 1, H0651: 1, H0539: 1, H0521: 1, S0406: 1, H0576: 1, L0743: 1, L0740: 1, L0750: 1, L0779: 1 and H0445: 1. 175 HPTVI96 636064 185 L0809: 5, L0779: 5, L0758: 5, L0769: 4, L0764: 4, L0777: 4, H0634: 3, L0748: 3, L0750: 3, L0731: 3, S0222: 2, L0163: 2, L0763: 2, L0772: 2, L0775: 2, L0776: 2, H0651: 2, L0749: 2, L0759: 2, H0657: 1, S0376: 1, S0300: 1, L0622: 1, H0427: 1, H0009: 1, L0471: 1, T0006: 1, H0424: 1, H0674: 1, H0708: 1, H0135: 1, H0413: 1, S0438: 1, L0771: 1, L0768: 1, L0794: 1, L0766: 1, L0774: 1, L0375: 1, L0806: 1, L0789: 1, H0648: 1, H0521: 1, S0406: 1 and H0506: 1. 176 HPWBA29 561956 186 AR313: 19, AR039: 14, AR218: 11, AR277: 11, AR089: 11, AR299: 10, AR096: 10, AR185: 10, AR300: 9, AR060: 8, AR219: 8, AR316: 8, AR055: 8, AR240: 8, AR104: 7, AR282: 6, AR283: 4, S0044: 1 177 HRDAI17 560720 187 H0031: 2, L0758: 2, H0013: 1, H0124: 1, L0369: 1, L0792: 1, S0216: 1, L0745: 1 and L0753: 1. 178 HRDDQ39 840405 188 AR313: 36, AR039: 33, AR185: 27, AR299: 20, AR089: 18, AR300: 17, AR096: 17, AR240: 16, AR218: 15, AR277: 14, AR316: 13, AR060: 11, AR219: 10, AR104: 9, AR055: 8, AR282: 7, AR283: 7, S0001: 2, H0436: 2, S0134: 1, H0657: 1, H0441: 1, H0009: 1, H0123: 1, H0050: 1, H0428: 1, H0124: 1, H0529: 1, H0521: 1 and H0352: 1. 179 HRDEX93 816046 189 AR104: 30, AR218: 25, AR219: 24, AR240: 22, AR096: 21, AR185: 17, AR039: 16, AR316: 16, AR313: 16, AR055: 14, AR060: 14, AR299: 13, AR089: 13, AR282: 9, AR277: 9, AR300: 9, AR283: 6, H0694: 12, L0748: 10, L0731: 7, L0754: 6, H0556: 5, L0758: 5, H0265: 4, S0420: 4, S0408: 4, L0517: 4, H0657: 3, H0618: 3, H0052: 3, H0083: 3, H0553: 3, H0494: 3, L0763: 3, L0666: 3, L0663: 3, S0126: 3, L0747: 3, H0295: 2, S0134: 2, S0418: 2, H0637: 2, S0046: 2, H0431: 2, H0545: 2, H0014: 2, H0271: 2, H0039: 2, H0424: 2, H0124: 2, H0641: 2, L0764: 2, L0766: 2, L0774: 2, L0775: 2, L0776: 2, L0655: 2, L0783: 2, L0665: 2, H0519: 2, H0522: 2, S0044: 2, L0755: 2, S0436: 2, L0595: 2, L0362: 2, H0543: 2, S0040: 1, H0740: 1, H0656: 1, S0212: 1, H0484: 1, H0661: 1, H0662: 1, S0360: 1, H0733: 1, H0619: 1, S0222: 1, H0486: 1, H0156: 1, H0575: 1, H0706: 1, H0253: 1, S0010: 1, S0346: 1, H0318: 1, H0596: 1, H0231: 1, H0046: 1, H0150: 1, H0081: 1, H0050: 1, H0012: 1, H0620: 1, L0163: 1, S0051: 1, T0010: 1, S6028: 1, H0266: 1, H0179: 1, H0292: 1, H0031: 1, H0644: 1, H0182: 1, H0617: 1, H0606: 1, H0673: 1, L0455: 1, L0456: 1, H0598: 1, H0038: 1, H0040: 1, H0616: 1, H0087: 1, T0067: 1, H0264: 1, T0041: 1, H0131: 1, H0647: 1, S0002: 1, L0772: 1, L0642: 1, L0662: 1, L0767: 1, L0657: 1, L0659: 1, L0382: 1, L5623: 1, L0664: 1, S0374: 1, H0593: 1, H0690: 1, H0682: 1, H0659: 1, H0658: 1, H0666: 1, H0651: 1, H0539: 1, H0521: 1, S0406: 1, H0576: 1, L0743: 1, L0740: 1, L0750: 1, L0779: 1 and H0445: 1. 180 HRTAP63 780698 190 AR219: 53, AR218: 46, AR313: 33, AR104: 28, AR096: 26, AR089: 25, AR316: 24, AR039: 20, AR299: 19, AR185: 18, AR300: 17, AR060: 17, AR282: 16, AR055: 15, AR240: 13, AR277: 10, AR283: 9, S0474: 28, H0521: 15, L0758: 14, L0752: 13, L0731: 13, L0755: 10, H0641: 9, L0766: 8, H0179: 6, L0748: 6, L0439: 6, L0759: 6, H0638: 5, S0222: 5, H0581: 5, L0662: 5, L0655: 5, H0436: 5, L0740: 5, L0777: 5, S0436: 5, H0457: 4, L0775: 4, L0809: 4, H0522: 4, L0742: 4, L0754: 4, L0747: 4, L0749: 4, L0750: 4, L0757: 4, H0580: 3, H0619: 3, H0052: 3, S0003: 3, H0038: 3, H0623: 3, L0666: 3, L0663: 3, S0053: 3, S0126: 3, S0434: 3, S0026: 3, S0212: 2, S0442: 2, S0408: 2, H0747: 2, S0476: 2, H0156: 2, L0021: 2, H0599: 2, S0010: 2, H0014: 2, S0214: 2, H0031: 2, H0644: 2, H0628: 2, S0036: 2, H0090: 2, H0616: 2, S0144: 2, S0002: 2, L0598: 2, L0764: 2, L0768: 2, L0774: 2, L0806: 2, L0653: 2, L0657: 2, L0659: 2, H0520: 2, H0547: 2, H0539: 2, H0710: 2, S0027: 2, L0779: 2, L0588: 2, L0592: 2, L0594: 2, L0366: 2, H0665: 2, H0739: 1, H0170: 1, T0002: 1, S0342: 1, H0717: 1, H0740: 1, S0114: 1, S0218: 1, H0650: 1, H0657: 1, S0282: 1, L3659: 1, S0418: 1, S0420: 1, L0005: 1, T0008: 1, H0742: 1, H0722: 1, H0735: 1, S0007: 1, S0046: 1, H0749: 1, L3388: 1, H0351: 1, H0406: 1, S0278: 1, H0461: 1, H0601: 1, H0586: 1, H0497: 1, H0574: 1, T0039: 1, L3655: 1, H0013: 1, H0427: 1, H0575: 1, H0590: 1, H0421: 1, S0049: 1, H0327: 1, H0545: 1, H0046: 1, H0572: 1, H0570: 1, H0050: 1, L0471: 1, H0373: 1, H0510: 1, H0375: 1, S6028: 1, H0266: 1, H0271: 1, H0719: 1, H0416: 1, S0340: 1, S0312: 1, H0615: 1, L0483: 1, T0006: 1, H0169: 1, H0674: 1, H0163: 1, H0591: 1, H0551: 1, H0264: 1, H0412: 1, H0059: 1, H0494: 1, S0015: 1, S0344: 1, UNKWN: 1, H0529: 1, L0520: 1, L0637: 1, L0761: 1, L0667: 1, L0772: 1, L0641: 1, L0648: 1, L0521: 1, L0794: 1, L0649: 1, L0803: 1, L0805: 1, L0783: 1, L0384: 1, L5622: 1, L0793: 1, L0664: 1, L0665: 1, S0052: 1, S0428: 1, S0216: 1, H0144: 1, L3811: 1, H0658: 1, H0670: 1, H0666: 1, H0672: 1, H0651: 1, L0355: 1, S0328: 1, S0152: 1, H0696: 1, S0406: 1, H0555: 1, S0028: 1, S0032: 1, L0744: 1, L0745: 1, L0780: 1, L0362: 1, H0422: 1 and H0721: 1. 181 HSAVW42 637660 191 AR277: 28, AR283: 24, AR219: 20, AR055: 17, AR218: 16, AR316: 16, AR282: 16, AR313: 15, AR089: 15, AR104: 13, AR299: 12, AR185: 11, AR240: 11, AR096: 11, AR039: 10, AR300: 9, AR060: 8, H0412: 2, S0114: 1, S0222: 1, H0169: 1, L0520: 1, L0805: 1, L0776: 1, L0750: 1 and L0777: 1. 182 HSAWN53 634697 192 AR277: 14, AR313: 13, AR219: 10, AR299: 9, AR039: 9, AR089: 9, AR055: 9, AR185: 9, AR104: 8, AR218: 8, AR300: 8, AR283: 8, AR316: 8, AR282: 8, AR060: 8, AR096: 7, AR240: 6, S0114: 1 183 HSAWZ40 634000 193 AR283: 11, AR039: 8, AR218: 8, AR060: 8, AR219: 8, AR313: 8, AR055: 7, AR089: 7, AR185: 7, AR096: 6, AR299: 6, AR316: 6, AR240: 6, AR277: 5, AR282: 5, AR104: 5, AR300: 4, S0114: 1 184 HSAYC41 688057 194 S0114: 1, H0411: 1, H0179: 1, L0665: 1 and H0435: 1. 185 HSDBI90 853376 195 AR055: 5, AR282: 4, AR060: 4, AR104: 3, AR240: 3, AR218: 3, AR283: 2, AR185: 2, AR277: 2, AR219: 2, AR300: 2, AR089: 2, AR096: 2, AR039: 2, AR316: 1, AR299: 1, L0439: 5, L0438: 2, S6024: 1, H0052: 1, H0009: 1, H0051: 1, H0424: 1, S0352: 1, L0794: 1, L0803: 1, L0790: 1 and S0106: 1. 186 HSHAX04 812178 196 AR299: 18, AR219: 18, AR104: 17, AR218: 17, AR277: 17, AR313: 16, AR316: 15, AR283: 14, AR055: 13, AR096: 13, AR039: 12, AR240: 12, AR060: 12, AR282: 11, AR089: 11, AR185: 10, AR300: 10, L0731: 6, H0265: 4, L0483: 4, H0424: 4, H0253: 3, H0318: 3, L0769: 3, L0774: 3, L0776: 3, S0037: 3, L0742: 3, L0750: 3, L0755: 3, S0360: 2, H0581: 2, H0266: 2, H0213: 2, H0124: 2, H0413: 2, L0766: 2, L0659: 2, L0809: 2, S3014: 2, L0749: 2, L0757: 2, L0758: 2, L0759: 2, L0596: 2, L0595: 2, H0543: 2, H0422: 2, H0686: 1, H0685: 1, S0040: 1, H0295: 1, H0294: 1, S0430: 1, H0638: 1, S0418: 1, S0420: 1, S0354: 1, S0358: 1, S0376: 1, S0045: 1, H0586: 1, H0497: 1, H0333: 1, H0486: 1, H0069: 1, H0575: 1, H0618: 1, H0052: 1, H0085: 1, H0009: 1, S0051: 1, H0083: 1, H0284: 1, H0428: 1, H0417: 1, H0553: 1, H0628: 1, H0038: 1, H0280: 1, H0494: 1, H0625: 1, S0150: 1, S0426: 1, L0667: 1, L0646: 1, L0764: 1, L0773: 1, L0648: 1, L0767: 1, L0768: 1, L0375: 1, L0806: 1, L0519: 1, L0666: 1, L0663: 1, H0698: 1, H0689: 1, H0539: 1, H0518: 1, S0027: 1, S0028: 1, L0747: 1, L0752: 1, H0707: 1, L0597: 1, L0581: 1, L0361: 1, H0653: 1, H0542: 1 and H0506: 1. 187 HSKDR27 580874 197 AR055: 9, AR104: 9, AR218: 7, AR060: 7, AR299: 6, AR185: 6, AR039: 6, AR240: 5, AR089: 5, AR219: 5, AR300: 5, AR283: 5, AR316: 4, AR313: 4, AR096: 3, AR277: 3, AR282: 2, S0027: 95, S0192: 54, S3014: 53, S0126: 42, S0040: 35, H0424: 23, S0028: 22, S0037: 19, S3012: 16, H0213: 13, T0006: 12, H0250: 11, S0032: 11, L0744: 11, T0040: 10, H0124: 10, H0429: 10, L0740: 10, L0588: 10, L0754: 9, H0545: 8, H0280: 8, S0194: 8, S0196: 7, H0392: 6, T0039: 6, H0150: 6, H0039: 6, S0206: 6, L0743: 6, L0731: 6, S0342: 5, S0212: 5, S0045: 5, H0486: 5, H0575: 5, H0014: 5, H0090: 5, H0551: 5, H0100: 5, S0044: 5, S0011: 5, H0255: 4, H0318: 4, H0271: 4, S0022: 4, H0031: 4, H0181: 4, H0032: 4, H0038: 4, T0067: 4, S0124: 4, L0747: 4, L0749: 4, H0402: 3, H0309: 3, H0046: 3, S0250: 3, H0068: 3, H0087: 3, H0059: 3, S0142: 3, S0053: 3, H0419: 2, S0116: 2, S0408: 2, S0132: 2, S0278: 2, S0222: 2, H0331: 2, T0060: 2, H0069: 2, H0427: 2, H0599: 2, T0082: 2, H0253: 2, H0546: 2, H0086: 2, H0123: 2, H0024: 2, H0015: 2, H0510: 2, H0428: 2, T0023: 2, H0163: 2, H0063: 2, H0509: 2, L0772: 2, L0805: 2, S0052: 2, H0547: 2, H0518: 2, L0748: 2, L0751: 2, L0745: 2, L0750: 2, L0777: 2, L0755: 2, L0757: 2, H0445: 2, L0590: 2, L0599: 2, S0026: 2, S0242: 2, H0171: 1, H0265: 1, H0716: 1, H0294: 1, S0298: 1, H0662: 1, H0450: 1, S0360: 1, H0329: 1, S0046: 1, H0411: 1, S6022: 1, H0431: 1, H0357: 1, H0455: 1, H0586: 1, H0587: 1, L0021: 1, H0042: 1, T0048: 1, H0505: 1, H0052: 1, H0251: 1, H0235: 1, H0231: 1, H0544: 1, H0050: 1, H0051: 1, H0071: 1, H0083: 1, H0060: 1, H0266: 1, H0188: 1, H0292: 1, S0214: 1, H0328: 1, H0033: 1, H0417: 1, H0553: 1, H0628: 1, H0617: 1, H0606: 1, H0383: 1, H0212: 1, H0388: 1, H0135: 1, H0040: 1, H0487: 1, H0413: 1, T0069: 1, H0560: 1, H0538: 1, S0210: 1, L0763: 1, L0646: 1, L0641: 1, L0649: 1, L0803: 1, L0652: 1, L0629: 1, L0659: 1, L0787: 1, L0665: 1, H0435: 1, H0528: 1, H0521: 1, H0555: 1, L0779: 1, L0581: 1, S0276: 1 and H0008: 1. 188 HSNBM34 635131 198 AR185: 18, AR039: 18, AR299: 15, AR104: 11, AR055: 9, AR277: 9, AR060: 8, AR096: 8, AR282: 8, AR300: 7, AR218: 7, AR240: 7, AR313: 6, AR316: 6, AR219: 5, AR283: 4, AR089: 4, H0599: 9, H0144: 8, H0457: 7, H0266: 7, H0494: 6, H0046: 5, H0031: 5, H0553: 5, L5622: 5, H0593: 5, H0521: 5, H0734: 4, H0013: 4, H0135: 4, S0436: 4, S0212: 3, H0069: 3, H0036: 3, H0052: 3, S0022: 3, H0708: 3, H0551: 3, H0696: 3, S0434: 3, H0713: 2, H0717: 2, S0418: 2, S0354: 2, H0580: 2, H0728: 2, H0733: 2, H0550: 2, H0587: 2, H0559: 2, H0706: 2, H0253: 2, H0355: 2, H0039: 2, S0364: 2, H0038: 2, H0634: 2, H0433: 2, H0560: 2, S0440: 2, H0646: 2, L3818: 2, S0002: 2, L0506: 2, L5623: 2, H0547: 2, S0126: 2, H0518: 2, H0436: 2, H0478: 2, S3014: 2, L0601: 2, H0506: 2, H0265: 1, H0556: 1, T0002: 1, S0114: 1, H0583: 1, S0116: 1, S0356: 1, S0442: 1, S0358: 1, S0376: 1, S0360: 1, S0408: 1, H0340: 1, H0742: 1, H0735: 1, S0132: 1, S0476: 1, H0619: 1, S0278: 1, S0222: 1, H0409: 1, H0602: 1, H0592: 1, H0586: 1, H0486: 1, H0270: 1, S0280: 1, H0042: 1, H0575: 1, H0122: 1, H0590: 1, S0010: 1, T0048: 1, H0318: 1, S0474: 1, S0049: 1, H0173: 1, H0085: 1, H0597: 1, H0231: 1, H0327: 1, H0544: 1, H0123: 1, H0050: 1, H0095: 1, H0373: 1, L0163: 1, H0051: 1, T0010: 1, T0023: 1, H0213: 1, L0142: 1, H0383: 1, S0366: 1, H0163: 1, H0040: 1, H0616: 1, H0087: 1, H0379: 1, S0038: 1, T0042: 1, S0150: 1, S0144: 1, H0529: 1, L0369: 1, L3905: 1, L0766: 1, L0775: 1, L0532: 1, H0693: 1, H0689: 1, H0670: 1, L0602: 1, H0522: 1, S0044: 1, L0611: 1, S0027: 1, S0028: 1, L0741: 1, L0743: 1, L0748: 1, L0439: 1, L0592: 1, L0485: 1, L0608: 1, L0366: 1, H0668: 1, H0542: 1, H0543: 1 and H0423: 1. 189 HSRFD18 840771 199 AR055: 2, AR039: 1, L0754: 10, S0422: 5, S0022: 4, L0803: 4, L0748: 4, L0747: 4, L0591: 4, H0486: 3, L0766: 3, L0805: 3, L0526: 3, L0665: 3, S0434: 3, S0212: 2, S0444: 2, S0360: 2, S0222: 2, L3816: 2, H0013: 2, H0596: 2, L0471: 2, H0166: 2, H0591: 2, H0509: 2, L0646: 2, L0662: 2, L0659: 2, L0666: 2, L0664: 2, S0374: 2, L0779: 2, L0777: 2, L0759: 2, S0436: 2, H0624: 1, H0170: 1, S0114: 1, S0001: 1, H0671: 1, H0663: 1, H0402: 1, H0305: 1, S0442: 1, S0408: 1, H0329: 1, H0742: 1, L3387: 1, H0581: 1, H0421: 1, H0194: 1, H0263: 1, H0597: 1, H0569: 1, H0355: 1, H0510: 1, H0179: 1, H0687: 1, H0615: 1, L0483: 1, H0553: 1, H0644: 1, H0673: 1, H0674: 1, H0100: 1, S0450: 1, H0714: 1, L0763: 1, L0770: 1, L0761: 1, L0649: 1, L0776: 1, L0518: 1, L0790: 1, L0791: 1, L0792: 1, L0663: 1, H0547: 1, H0670: 1, H0521: 1, H0696: 1, S0406: 1, H0555: 1, H0478: 1, L0780: 1, H0707: 1, S0276: 1 and H0543: 1. 190 HSSEF77 658725 200 H0617: 7, L0750: 7, H0556: 5, L0769: 5, L0783: 5, L0758: 5, L0759: 5, L0665: 4, L0741: 4, S0132: 3, L0761: 3, L0742: 3, L0439: 3, L0755: 3, L0592: 3, H0618: 2, H0620: 2, H0038: 2, L0771: 2, L0662: 2, L0659: 2, L0666: 2, S0126: 2, H0670: 2, S0328: 2, S0380: 2, L0747: 2, L0753: 2, L0731: 2, H0395: 1, H0295: 1, H0294: 1, H0657: 1, H0656: 1, H0341: 1, H0484: 1, H0663: 1, H0638: 1, S0356: 1, S0444: 1, H0741: 1, L3271: 1, H0549: 1, H0550: 1, H0370: 1, H0455: 1, H0632: 1, H0486: 1, T0039: 1, T0112: 1, H0156: 1, H0581: 1, H0052: 1, H0545: 1, H0046: 1, H0150: 1, H0081: 1, S0051: 1, H0107: 1, H0061: 1, H0188: 1, H0288: 1, S0250: 1, H0428: 1, H0135: 1, H0163: 1, H0090: 1, H0616: 1, T0004: 1, S0438: 1, L0770: 1, L0796: 1, L0637: 1, L0772: 1, L0372: 1, L0646: 1, L0521: 1, L0768: 1, L0766: 1, L5574: 1, L0774: 1, L0775: 1, L0375: 1, L0806: 1, L0776: 1, L0807: 1, L0657: 1, L0658: 1, L0540: 1, L0384: 1, L0809: 1, L0663: 1, L0438: 1, H0672: 1, H0754: 1, S0188: 1, S0406: 1, H0436: 1, H0576: 1, S3014: 1, L0748: 1, L0779: 1, L0757: 1 and H0506: 1. 191 HSSGJ58 747714 201 AR277: 4, AR282: 3, AR055: 2, AR185: 2, AR299: 2, AR104: 2, AR218: 2, AR060: 2, AR240: 2, AR089: 2, AR219: 1, AR283: 1, AR039: 1, AR300: 1, AR316: 1, AR313: 1, L0749: 2, H0135: 1, L0558: 1 and L0748: 1. 192 HSVBD37 637110 202 AR219: 111, AR218: 98, AR089: 46, AR185: 35, AR299: 32, AR313: 32, AR096: 30, AR277: 30, AR316: 30, AR060: 28, AR283: 27, AR104: 26, AR055: 26, AR039: 23, AR240: 22, AR282: 21, AR300: 19, S0136: 115, L0731: 10, L0803: 9, S0026: 9, S0358: 7, L0439: 7, H0624: 6, S0418: 6, L0805: 6, H0619: 5, L0659: 5, L0666: 5, L0754: 5, L0756: 5, H0170: 4, S0360: 4, H0553: 4, L0662: 4, H0547: 4, L0750: 4, L0779: 4, H0351: 3, H0486: 3, H0046: 3, H0050: 3, L0471: 3, H0266: 3, H0623: 3, L0770: 3, H0144: 3, H0520: 3, S0380: 3, S0040: 2, H0295: 2, H0661: 2, S0420: 2, S0376: 2, H0722: 2, H0369: 2, H0592: 2, H0574: 2, H0013: 2, H0575: 2, H0051: 2, S0022: 2, H0615: 2, H0032: 2, S0438: 2, S0440: 2, L0598: 2, L0769: 2, L0774: 2, L0776: 2, L0518: 2, L0663: 2, H0726: 2, S0126: 2, H0539: 2, H0696: 2, H0555: 2, L0740: 2, L0747: 2, L0753: 2, L0593: 2, H0686: 1, S0212: 1, H0484: 1, H0671: 1, H0662: 1, S0356: 1, S0442: 1, S0354: 1, S0444: 1, S0476: 1, H0645: 1, S0222: 1, H0441: 1, H0586: 1, H0587: 1, H0333: 1, H0632: 1, S0280: 1, L0021: 1, H0599: 1, H0590: 1, H0309: 1, L0040: 1, H0544: 1, H0545: 1, H0019: 1, S0051: 1, H0275: 1, H0375: 1, S6028: 1, S0250: 1, H0328: 1, H0428: 1, H0031: 1, H0111: 1, H0628: 1, S0364: 1, H0135: 1, H0616: 1, H0551: 1, H0268: 1, H0100: 1, H0494: 1, H0652: 1, S0210: 1, L0763: 1, L5566: 1, L0646: 1, L0800: 1, L0764: 1, L0771: 1, L0768: 1, L0649: 1, L0804: 1, L0775: 1, L0806: 1, L0527: 1, L0636: 1, L0783: 1, L0790: 1, S0296: 1, H0693: 1, H0519: 1, H0690: 1, H0682: 1, H0684: 1, H0648: 1, H0672: 1, S0454: 1, S0013: 1, H0626: 1, H0627: 1, S0028: 1, L0744: 1, L0777: 1, L0755: 1, L0757: 1, L0758: 1, L0759: 1, S0434: 1, S0436: 1, L0592: 1, H0667: 1, S0194: 1 and H0506: 1. 193 HSYBI06 740766 203 AR313: 46, AR039: 40, AR096: 25, AR185: 20, AR300: 20, AR089: 20, AR299: 18, AR104: 18, AR240: 17, AR316: 17, AR219: 16, AR277: 16, AR218: 14, AR060: 12, AR282: 10, AR055: 4, AR283: 3, H0159: 2, H0663: 2, H0024: 2, H0059: 2, H0543: 2, H0556: 1, H0222: 1, L3643: 1, H0255: 1, H0431: 1, T0039: 1, H0599: 1, S0010: 1, T0048: 1, H0251: 1, H0266: 1, H0032: 1, H0551: 1, H0100: 1, S0015: 1, S0370: 1, H0743: 1, L0369: 1, L0627: 1, L0519: 1, L0663: 1, L0665: 1, H0691: 1, H0696: 1, H0627: 1, S0028: 1, L0744: 1, L0740: 1, L0777: 1, S0434: 1, L0588: 1, L0604: 1 and H0422: 1. 194 HT4FV41 853400 204 AR244: 10, AR185: 10, AR204: 9, AR275: 9, AR202: 9, AR194: 9, AR052: 9, AR271: 8, AR246: 8, AR289: 8, AR219: 7, AR316: 7, AR104: 7, AR198: 7, AR089: 7, AR277: 7, AR310: 7, AR060: 7, AR309: 7, AR206: 7, AR039: 7, AR229: 7, AR282: 7, AR053: 7, AR283: 7, AR269: 6, AR205: 6, AR270: 6, AR312: 6, AR184: 6, AR186: 6, AR299: 6, AR096: 6, AR240: 6, AR251: 6, AR274: 6, AR182: 6, AR055: 6, AR033: 6, AR291: 6, AR218: 6, AR243: 6, AR266: 6, AR290: 6, AR192: 5, AR268: 5, AR280: 5, AR247: 5, AR213: 5, AR298: 5, AR231: 5, AR273: 5, AR313: 5, AR234: 5, AR284: 5, AR296: 5, AR061: 5, AR248: 5, AR238: 5, AR285: 5, AR183: 5, AR253: 5, AR300: 5, AR267: 4, AR286: 4, AR315: 4, AR175: 4, AR293: 4, AR294: 4, AR177: 4, AR249: 4, AR281: 3, AR227: 3, AR233: 3, AR292: 3, AR263: 3, AR265: 3, AR232: 3, AR295: 3, AR226: 3, AR237: 3, AR258: 2, AR314: 2, AR256: 1, AR259: 1, AR179: 1, AR241: 1, L0794: 10, L0800: 7, L0769: 6, L0751: 6, L0761: 4, L0809: 4, H0521: 4, L0439: 4, H0585: 3, H0617: 3, H0494: 3, L0659: 3, L0665: 3, L0777: 3, H0265: 2, H0255: 2, S0354: 2, S0376: 2, H0370: 2, H0069: 2, H0083: 2, H0040: 2, L0770: 2, L0764: 2, L0662: 2, L5622: 2, L0666: 2, L0663: 2, L0438: 2, L0743: 2, L0780: 2, S0436: 2, H0667: 2, H0423: 2, S0040: 1, H0713: 1, H0295: 1, H0254: 1, H0638: 1, S0418: 1, S0420: 1, S0360: 1, H0734: 1, S0046: 1, S0476: 1, H0587: 1, H0635: 1, H0575: 1, H0004: 1, H0618: 1, H0052: 1, H0194: 1, H0544: 1, H0545: 1, H0373: 1, T0010: 1, H0267: 1, H0179: 1, H0622: 1, L0194: 1, H0181: 1, H0124: 1, H0087: 1, H0412: 1, H0413: 1, H0646: 1, S0144: 1, L0369: 1, L0640: 1, L0763: 1, L0772: 1, L0646: 1, L0643: 1, L0644: 1, L0768: 1, L0803: 1, L0805: 1, L0655: 1, L0518: 1, L0783: 1, L0384: 1, L0789: 1, S0052: 1, L2263: 1, L0710: 1, H0547: 1, H0682: 1, S0152: 1, H0187: 1, H0727: 1, S0390: 1, L0752: 1, L0757: 1, L0758: 1, H06651, H0543: 1, H0422: 1 and S0424: 1. 195 HT5GR59 801930 205 AR240: 19, AR096: 15, AR316: 10, AR300: 9, AR055: 9, AR039: 8, AR313: 8, AR282: 8, AR277: 7, AR185: 7, AR060: 7, AR219: 7, AR218: 6, AR299: 6, AR104: 6, AR283: 6, AR089: 5, H0584: 36, H0585: 22, H0141: 11, H0167: 9, H0457: 7, H0521: 6, S0474: 4, H0575: 3, L0731: 3, H0265: 2, H0556: 2, H0581: 2, L0761: 2, H0543: 2, H0140: 1, H0638: 1, S0358: 1, S0140: 1, H0747: 1, H0619: 1, H0497: 1, H0559: 1, H0069: 1, H0635: 1, H0427: 1, S0280: 1, H0252: 1, H0477: 1, L0667: 1, L0768: 1, L0775: 1, L0659: 1, L0791: 1, L0792: 1, S0053: 1, L0777: 1, L0758: 1, H0445: 1 and H0506: 1. 196 HTDAA78 566861 206 AR240: 12, AR219: 12, AR039: 10, AR316: 10, AR218: 9, AR096: 8, AR283: 8, AR282: 8, AR313: 7, AR055: 7, AR089: 6, AR104: 6, AR300: 6, AR299: 6, AR277: 5, AR060: 4, AR185: 3, H0477: 1 197 HTEAG62 812332 207 AR310: 2, AR282: 2, AR206: 2, AR273: 2, AR186: 1, AR295: 1, AR294: 1, AR175: 1, L0766: 6, H0038: 5, L0758: 4, H0616: 3, S0422: 2, L0779: 2, L0752: 2, H0638: 1, S0376: 1, S0132: 1, L3388: 1, H0250: 1, L0564: 1, L0794: 1, L0803: 1, L0666: 1, L0777: 1, L0755: 1, H0595: 1, S0434: 1 and H0542: 1. 198 HTECB02 806305 208 AR283: 34, AR104: 20, AR219: 12, AR240: 12, AR089: 12, AR218: 12, AR282: 11, AR299: 10, AR055: 10, AR039: 9, AR060: 9, AR096: 8, AR316: 8, AR185: 7, AR277: 6, AR300: 6, AR313: 6, S0358: 3, H0253: 3, T0010: 3, L0806: 3, L0747: 3, L0749: 3, H0265: 2, H0663: 2, H0036: 2, H0618: 2, L0764: 2, L5623: 2, L0666: 2, H0521: 2, L0759: 2, L0591: 2, L0604: 2, H0556: 1, S0114: 1, L0443: 1, S0408: 1, H0619: 1, S0222: 1, H0559: 1, T0039: 1, S0280: 1, L0021: 1, H0706: 1, H0196: 1, H0052: 1, H0545: 1, H0009: 1, H0172: 1, H0123: 1, H0024: 1, H0014: 1, S0338: 1, H0239: 1, H0428: 1, H0181: 1, H0708: 1, H0591: 1, H0038: 1, S0002: 1, L0796: 1, L3905: 1, L0761: 1, L0646: 1, L0766: 1, L0381: 1, L0803: 1, L0774: 1, L0775: 1, L0807: 1, L0517: 1, L0783: 1, L0384: 1, L0809: 1, L0545: 1, L5622: 1, L0788: 1, L0664: 1, L0447: 1, H0658: 1, S0027: 1, L0743: 1, L0744: 1, L0751: 1, L0754: 1, L0745: 1, L0746: 1, L0750: 1, L0752: 1, L0755: 1, L0758: 1, S0434: 1, H0665: 1 and H0542: 1. 199 HTEDJ28 762845 209 AR219: 24, AR218: 21, AR089: 19, AR055: 18, AR313: 16, AR299: 15, AR096: 13, AR316: 13, AR104: 13, AR060: 11, AR185: 11, AR283: 10, AR039: 9, AR277: 9, AR282: 9, AR300: 8, AR240: 7, L0747: 9, L0439: 8, L0809: 6, L0766: 5, L0750: 5, L0758: 5, L0740: 4, L0752: 4, L0731: 4, L0662: 3, H0547: 3, L0779: 3, L0777: 3, L0757: 3, H0375: 2, L0646: 2, L0774: 2, L0783: 2, H0144: 2, L0759: 2, S0442: 1, H0333: 1, T0060: 1, H0327: 1, H0399: 1, L0483: 1, H0038: 1, L0564: 1, S0382: 1, H0538: 1, H0743: 1, L0763: 1, L0638: 1, L0765: 1, L0771: 1, L0649: 1, L0522: 1, L0775: 1, L0655: 1, L0659: 1, L0792: 1, L0663: 1, L0438: 1, H0648: 1, L0756: 1, L0753: 1, L0596: 1, L0590: 1, L0592: 1, L0608: 1, H0423: 1 and S0460: 1. 200 HTEHU59 840385 210 AR313: 11, AR218: 10, AR219: 9, AR039: 7, AR316: 6, AR096: 6, AR104: 6, AR277: 5, AR299: 5, AR055: 5, AR282: 4, AR089: 4, AR283: 3, AR300: 3, AR060: 3, AR240: 3, AR185: 3, S0422: 6, H0038: 4, L0758: 4, L0754: 3, S0360: 2, H0024: 2, L0598: 2, L0766: 2, L0748: 2, L0747: 2, L0756: 2, H0583: 1, H0341: 1, S0418: 1, L0005: 1, H0741: 1, H0437: 1, H0369: 1, H0581: 1, H0194: 1, S0050: 1, H0271: 1, H0428: 1, T0006: 1, H0068: 1, H0412: 1, H0056: 1, H0494: 1, S0426: 1, L0772: 1, L0646: 1, L0662: 1, L0803: 1, L0806: 1, L0776: 1, L0655: 1, L0789: 1, L0792: 1, H0144: 1, S0374: 1, H0670: 1, H0627: 1, S0026: 1 and S0192: 1. 201 HTEJD29 695798 211 H0038: 2 202 HTEKM46 862069 212 S0422: 6, H0038: 4, L0758: 4, L0754: 3, S0360: 2, H0024: 2, L0598: 2, L0766: 2, L0748: 2, L0747: 2, L0756: 2, H0583: 1, H0341: 1, S0418: 1, L0005: 1, H0741: 1, H0437: 1, H0369: 1, H0581: 1, H0194: 1, S0050: 1, H0271: 1, H0428: 1, T0006: 1, H0068: 1, H0412: 1, H0056: 1, H0494: 1, S0426: 1, L0772: 1, L0646: 1, L0662: 1, L0803: 1, L0806: 1, L0776: 1, L0655: 1, L0789: 1, L0792: 1, H0144: 1, S0374: 1, H0670: 1, H0627: 1, S0026: 1 and S0192: 1. 203 HTENR63 877952 213 AR277: 32, AR283: 29, AR218: 25, AR219: 22, AR282: 21, AR316: 21, AR089: 20, AR313: 19, AR104: 18, AR055: 17, AR299: 16, AR096: 16, AR240: 16, AR185: 15, AR300: 14, AR039: 14, AR060: 11, L0748: 9, L0777: 6, L0439: 5, L0749: 5, L0766: 4, L0438: 4, L0755: 4, L0752: 3, L0594: 3, L3814: 2, S0212: 2, H0014: 2, H0032: 2, H0598: 2, H0038: 2, H0100: 2, L0775: 2, S0330: 2, L0754: 2, L0750: 2, L0731: 2, L0758: 2, L0759: 2, L0485: 2, S0192: 2, S0040: 1, H0583: 1, S0356: 1, H0733: 1, S0046: 1, H0747: 1, L3652: 1, H0613: 1, H0024: 1, H0373: 1, H0375: 1, H0179: 1, H0166: 1, H0673: 1, H0591: 1, H0616: 1, H0551: 1, H0412: 1, H0129: 1, H0529: 1, L0761: 1, L0771: 1, L0804: 1, L0784: 1, L0806: 1, L0655: 1, L0783: 1, L0666: 1, H0144: 1, L3811: 1, S0126: 1, S0328: 1, H0539: 1, S0152: 1, L0740: 1, L0756: 1, L0779: 1, L0757: 1, H0445: 1, L0599: 1 and S0026: 1. 204 HTGBK95 834490 214 AR277: 83, AR313: 74, AR219: 72, AR283: 69, AR316: 57, AR039: 49, AR218: 49, AR089: 48, AR299: 46, AR282: 42, AR104: 42, AR096: 42, AR185: 40, AR240: 39, AR055: 37, AR300: 32, AR060: 32, L0777: 5, S0444: 3, L0766: 3, L0803: 3, L0439: 3, S0360: 2, L0598: 2, L0666: 2, L0748: 2, T0049: 1, S0134: 1, S0116: 1, S0408: 1, L0717: 1, H0586: 1, H0486: 1, H0575: 1, H0510: 1, H0553: 1, H0560: 1, S0422: 1, L0763: 1, L0769: 1, L0521: 1, L0767: 1, L0768: 1, L0775: 1, L0663: 1, S0374: 1, L0438: 1, H0520: 1, H0682: 1, S0328: 1, S0406: 1, L0740: 1, S0192: 1 and H0543: 1. 205 HTGGM44 842856 215 AR246: 5, AR244: 5, AR184: 5, AR253: 5, AR309: 4, AR313: 4, AR186: 4, AR052: 3, AR206: 3, AR312: 3, AR310: 3, AR204: 3, AR274: 3, AR291: 3, AR060: 3, AR055: 3, AR229: 3, AR053: 3, AR292: 3, AR269: 3, AR061: 3, AR243: 3, AR205: 3, AR247: 3, AR213: 2, AR299: 2, AR294: 2, AR089: 2, AR273: 2, AR270: 2, AR266: 2, AR263: 2, AR039: 2, AR265: 2, AR293: 2, AR316: 2, AR275: 2, AR282: 2, AR267: 2, AR251: 2, AR277: 2, AR231: 2, AR283: 2, AR238: 2, AR284: 2, AR185: 2, AR271: 2, AR300: 2, AR182: 2, AR226: 2, AR096: 1, AR237: 1, AR033: 1, AR234: 1, AR290: 1, AR240: 1, AR241: 1, AR259: 1, AR194: 1, AR227: 1, AR104: 1, AR298: 1, L0748: 8, L0805: 2, L0599: 2, S0218: 1, T0040: 1, H0635: 1, S0250: 1, H0212: 1, H0634: 1, H0063: 1, S0002: 1, L0766: 1, H0144: 1, S0126: 1 and H0518: 1. 206 HTHBZ06 832477 216 AR218: 86, AR219: 83, AR089: 54, AR104: 50, AR282: 48, AR313: 44, AR283: 40, AR055: 34, AR316: 31, AR240: 29, AR185: 27, AR096: 23, AR060: 22, AR299: 22, AR300: 16, AR039: 15, AR277: 11, S0414: 9, L0005: 7, L0065: 7, S0360: 6, S0422: 5, H0545: 4, H0648: 4, L0777: 4, L0758: 4, H0716: 3, H0657: 3, S0474: 3, L0770: 3, L0666: 3, L0665: 3, L0600: 3, H0674: 2, H0494: 2, L0769: 2, L0638: 2, L0637: 2, L0768: 2, L0803: 2, L0774: 2, L0805: 2, L0664: 2, L0438: 2, H0520: 2, H0696: 2, L0751: 2, L0745: 2, L0749: 2, L0756: 2, L0779: 2, L0757: 2, L3643: 1, H0484: 1, H0671: 1, S0358: 1, L3649: 1, H0742: 1, H0741: 1, S0132: 1, L0623: 1, H0581: 1, S0214: 1, H0063: 1, H0412: 1, H0413: 1, S0002: 1, L0369: 1, L0796: 1, L0662: 1, L0766: 1, L0375: 1, L0656: 1, L0659: 1, L0647: 1, L3872: 1, L0663: 1, H0684: 1, S0328: 1, S0350: 1, H0436: 1, L0743: 1, L0754: 1, L0755: 1, L0731: 1, S0031: 1, S0436: 1, L0485: 1, L0608: 1, L0362: 1, H0506: 1 and H0352: 1. 207 HTLBT80 840045 217 AR251: 22, AR273: 18, AR053: 18, AR309: 16, AR310: 16, AR183: 15, AR313: 15, AR274: 15, AR263: 15, AR247: 15, AR312: 14, AR314: 14, AR266: 14, AR265: 14, AR219: 14, AR175: 13, AR218: 13, AR285: 12, AR280: 12, AR182: 12, AR268: 12, AR293: 12, AR213: 12, AR052: 12, AR292: 11, AR290: 11, AR286: 11, AR267: 11, AR277: 11, AR289: 11, AR315: 11, AR296: 11, AR256: 11, AR295: 11, AR177: 10, AR291: 10, AR269: 10, AR271: 10, AR284: 10, AR096: 9, AR243: 9, AR270: 9, AR299: 9, AR283: 9, AR249: 9, AR300: 9, AR033: 9, AR253: 9, AR238: 9, AR184: 8, AR179: 8, AR248: 8, AR231: 8, AR298: 8, AR234: 8, AR061: 8, AR226: 8, AR282: 8, AR232: 8, AR229: 8, AR316: 8, AR258: 8, AR259: 7, AR233: 7, AR240: 7, AR186: 7, AR294: 7, AR185: 7, AR198: 7, AR237: 7, AR275: 6, AR281: 6, AR039: 6, AR192: 6, AR227: 6, AR089: 6, AR104: 6, AR246: 6, AR055: 6, AR244: 6, AR202: 5, AR204: 5, AR060: 5, AR206: 4, AR205: 4, AR241: 4, AR194: 1, L0659: 6, H0556: 4, H0521: 4, L0439: 4, L0745: 4, L0759: 4, H0657: 3, S0360: 3, L0761: 3, L0662: 3, L0766: 3, L0809: 3, H0549: 2, H0392: 2, H0253: 2, H0581: 2, H0620: 2, H0051: 2, H0551: 2, H0494: 2, L0770: 2, L0794: 2, L0649: 2, L0665: 2, H0520: 2, S0032: 2, L0741: 2, L0743: 2, L0748: 2, L0747: 2, L0779: 2, L0758: 2, L0605: 2, H0650: 1, H0484: 1, H0254: 1, H0402: 1, S0358: 1, H0580: 1, H0741: 1, S0007: 1, S0132: 1, S0476: 1, H0393: 1, H0369: 1, H0550: 1, H0409: 1, H0256: 1, H0250: 1, H0042: 1, H0036: 1, H0318: 1, S0049: 1, H0050: 1, H0014: 1, H0375: 1, S6028: 1, H0266: 1, H0292: 1, H0428: 1, H0622: 1, H0031: 1, H0617: 1, L0456: 1, H0135: 1, H0040: 1, H0379: 1, H0264: 1, H0056: 1, H0623: 1, H0100: 1, H0633: 1, S0002: 1, H0529: 1, L0762: 1, L5575: 1, L0772: 1, L0646: 1, L0771: 1, L0773: 1, L0767: 1, L0768: 1, L0803: 1, L0805: 1, L0653: 1, L5622: 1, L4501: 1, L0666: 1, H0689: 1, H0690: 1, H0682: 1, H0670: 1, H0522: 1, S0044: 1, H0436: 1, S0027: 1, L0754: 1, L0749: 1, L0753: 1, L0731: 1, S0436: 1, H0653: 1, S0192: 1, H0542: 1, H0543: 1, H0423: 1 and S0424: 1. 208 HTLCX82 847091 218 L0803: 4, L0805: 4, L0758: 4, S0422: 3, H0255: 2, H0747: 2, L0769: 2, L0774: 2, L0666: 2, L0665: 2, L0439: 2, L0777: 2, L0731: 2, S0042: 2, H0265: 1, H0686: 1, H0662: 1, S0442: 1, L3387: 1, H0156: 1, H0253: 1, H0009: 1, H0571: 1, S6028: 1, S0214: 1, H0328: 1, H0494: 1, L0773: 1, L0766: 1, L0809: 1, L0788: 1, L0792: 1, L0663: 1, L0438: 1, H0518: 1, L0749: 1, L0779: 1, L0755: 1, H0595: 1 and H0707: 1. 209 HTLDU78 637702 219 L0758: 3, H0253: 1 and L0779: 1. 210 HTLEV48 723799 220 S0366: 4, L0623: 1 and H0253: 1. HTLEV48 566786 259 211 HTLFA13 535937 221 AR313: 11, AR089: 10, AR039: 9, AR096: 8, AR299: 8, AR282: 7, AR277: 7, AR283: 7, AR104: 7, AR219: 7, AR060: 7, AR270: 7, AR316: 6, AR218: 6, AR310: 6, AR300: 6, AR183: 5, AR233: 5, AR294: 5, AR185: 5, AR237: 5, AR226: 5, AR055: 5, AR238: 5, AR231: 4, AR227: 4, AR296: 4, AR251: 4, AR312: 4, AR240: 4, AR033: 4, AR269: 4, AR290: 3, AR285: 3, AR052: 3, AR184: 3, AR295: 3, AR258: 3, AR186: 3, AR292: 3, AR274: 2, AR205: 2, AR179: 2, AR053: 2, AR061: 2, AR206: 2, AR309: 2, AR293: 2, AR266: 2, AR273: 2, AR259: 1, AR194: 1, AR234: 1, AR182: 1, AR232: 1, AR241: 1, AR284: 1, H0253: 2 and S0011: 1. 212 HTLGI89 835069 222 AR283: 67, AR277: 61, AR219: 56, AR282: 51, AR104: 48, AR240: 47, AR316: 46, AR218: 45, AR313: 44, AR089: 42, AR096: 40, AR185: 37, AR299: 36, AR055: 34, AR300: 32, AR039: 32, AR060: 31, L0758: 16, L0748: 10, H0620: 7, L0731: 6, H0246: 5, S0007: 4, H0253: 4, L0769: 4, L0754: 4, H0052: 3, H0100: 3, L0638: 3, L5575: 3, L0766: 3, L0650: 3, L0774: 3, S0152: 3, S3014: 3, L0439: 3, H0265: 2, H0556: 2, T0002: 2, S6024: 2, H0656: 2, H0341: 2, S0212: 2, S0376: 2, H0619: 2, H0261: 2, S0222: 2, H0318: 2, H0196: 2, H0012: 2, T0010: 2, H0068: 2, H0551: 2, H0413: 2, H0494: 2, L0770: 2, L5565: 2, L3905: 2, L0768: 2, L0776: 2, S3012: 2, L0741: 2, L0749: 2, L0750: 2, L0759: 2, S0434: 2, L0608: 2, L0595: 2, H0352: 2, S0040: 1, L0760: 1, S0116: 1, S0282: 1, H0638: 1, S0418: 1, S0356: 1, S0444: 1, H0730: 1, H0747: 1, S0476: 1, H0393: 1, H0549: 1, H0550: 1, H0592: 1, H0333: 1, H0486: 1, T0114: 1, H0250: 1, H0069: 1, S0280: 1, H0156: 1, H0599: 1, H0575: 1, H0036: 1, H0618: 1, H0597: 1, H0178: 1, N0006: 1, H0563: 1, H0197: 1, H0199: 1, H0051: 1, H0083: 1, H0060: 1, H0188: 1, H0290: 1, H0284: 1, H0428: 1, H0622: 1, L0483: 1, H0124: 1, H0135: 1, H0163: 1, H0040: 1, H0264: 1, H0412: 1, L0564: 1, H0130: 1, H0641: 1, S0144: 1, S0002: 1, L0763: 1, L0761: 1, L0372: 1, L0643: 1, L0764: 1, L0771: 1, L0648: 1, L0767: 1, L0803: 1, L0804: 1, L0375: 1, L0378: 1, L0659: 1, L0544: 1, L0665: 1, H0703: 1, L0352: 1, H0670: 1, S0328: 1, S0330: 1, H0753: 1, H0522: 1, H0134: 1, S0027: 1, L0747: 1, L0756: 1, L0777: 1, L0753: 1, S0260: 1, H0445: 1, S0436: 1, L0597: 1, H0653: 1 and S0194: 1. 213 HTNBK13 831967 223 L0779: 5, L0731: 4, L0593: 4, H0046: 3, L0776: 3, L0666: 3, H0031: 2, L0772: 2, L0774: 2, L0805: 2, H0670: 2, L0439: 2, L0754: 2, L0777: 2, L0758: 2, L0590: 2, T0002: 1, L0717: 1, H0632: 1, L0622: 1, T0082: 1, H0581: 1, H0263: 1, T0115: 1, H0597: 1, L0471: 1, H0012: 1, H0620: 1, H0163: 1, T0067: 1, L0770: 1, L0637: 1, L0388: 1, L0657: 1, L0382: 1, L0664: 1, S0126: 1, H0660: 1, S0378: 1, H0521: 1, L0747: 1, L0750: 1, L0756: 1, L0752: 1, L0755: 1, L07591, S0031: 1, L0599: 1 and L0603: 1. 214 HTOAM11 664508 224 AR313: 30, AR039: 27, AR185: 18, AR299: 16, AR300: 13, AR277: 13, AR096: 13, AR089: 12, AR218: 11, AR219: 11, AR316: 9, AR240: 9, AR104: 8, AR060: 7, AR055: 6, AR282: 6, AR283: 3, S0010: 1 and H0264: 1. 215 HTODH83 580884 225 AR055: 4, AR060: 4, AR283: 2, AR039: 2, AR104: 2, AR219: 2, AR299: 2, AR185: 2, AR282: 1, AR089: 1, AR316: 1, AR240: 1, AR096: 1, AR277: 1, H0264: 1 216 HTODN35 570901 226 AR104: 20, AR185: 11, AR055: 11, AR060: 10, AR089: 10, AR299: 10, AR240: 9, AR277: 8, AR282: 8, AR313: 7, AR300: 7, AR316: 7, AR283: 5, AR096: 5, AR218: 4, AR219: 4, AR039: 3, H0264: 1 217 HTPCO75 853645 227 AR104: 12, AR219: 11, AR089: 9, AR039: 9, AR282: 8, AR218: 8, AR313: 8, AR060: 8, AR300: 8, AR055: 7, AR316: 7, AR277: 7, AR299: 7, AR096: 7, AR185: 6, AR240: 5, AR283: 4, H0039: 5, L0756: 5, S0448: 3, L0805: 3, L0759: 3, H0265: 2, S0354: 2, L0471: 2, H0674: 2, S0422: 2, L0794: 2, L0517: 2, L0666: 2, L0779: 2, L0777: 2, L0758: 2, H0170: 1, H0556: 1, S0342: 1, S0134: 1, H0637: 1, H0599: 1, H0318: 1, H0263: 1, H0596: 1, H0252: 1, H0428: 1, H0673: 1, H0040: 1, H0264: 1, H0268: 1, H0773: 1, H0538: 1, L0764: 1, L0768: 1, L0766: 1, L0804: 1, L0774: 1, L0652: 1, L0527: 1, L0809: 1, L0519: 1, L0791: 1, H0144: 1, H0520: 1, H0519: 1, H0689: 1, H0648: 1, S0028: 1, L0439: 1, L0731: 1, H0444: 1, H0445: 1, S0434: 1, S0026: 1, S0242: 1 and H0543: 1. 218 HTTCB60 853401 228 L0794: 11, L0809: 11, L0750: 9, L0805: 8, L0791: 7, L0747: 7, L0800: 6, L0758: 6, L0759: 6, H0620: 5, L0749: 5, S0358: 4, H0135: 4, L0769: 4, L0659: 4, L0780: 4, H0556: 3, L0471: 3, H0040: 3, L0804: 3, S0360: 2, H0393: 2, H0550: 2, H0592: 2, H0333: 2, S0049: 2, H0124: 2, S0438: 2, L0771: 2, L0662: 2, L0803: 2, L4501: 2, H0547: 2, L3832: 2, L0779: 2, L0755: 2, L0731: 2, S0434: 2, L0603: 2, H0506: 2, H0713: 1, H0717: 1, H0294: 1, H0662: 1, H0729: 1, H0734: 1, S0045: 1, H0607: 1, H0586: 1, H0587: 1, L3816: 1, T0040: 1, L3653: 1, S0280: 1, H0590: 1, S0010: 1, H0581: 1, H0251: 1, H0041: 1, H0565: 1, H0570: 1, H0123: 1, H0081: 1, H0050: 1, H0188: 1, H0039: 1, H0622: 1, H0038: 1, H0063: 1, H0412: 1, H0413: 1, S0440: 1, S0210: 1, S0002: 1, L0763: 1, L0770: 1, L3905: 1, L0761: 1, L0641: 1, L0768: 1, L0766: 1, L0375: 1, L0806: 1, L0776: 1, L0789: 1, L0790: 1, L0666: 1, L0663: 1, L0665: 1, L2258: 1, L2654: 1, H0520: 1, H0660: 1, H0672: 1, H0539: 1, S0380: 1, H0521: 1, H0696: 1, H0555: 1, L0744: 1, L0748: 1, L0757: 1, H0445: 1, L0584: 1, L0589: 1, S0242: 1, S0194: 1, H0008: 1 and H0352: 1. 219 HTTDN24 766485 229 AR218: 21, AR219: 20, AR089: 15, AR300: 14, AR316: 14, AR185: 13, AR313: 13, AR277: 13, AR282: 13, AR039: 12, AR299: 11, AR096: 11, AR055: 10, AR104: 8, AR240: 7, AR060: 7, AR283: 6 220 HTTEE41 840950 230 AR219: 84, AR218: 59, AR316: 43, AR313: 32, AR104: 24, AR089: 24, AR185: 24, AR039: 23, AR096: 23, AR299: 21, AR055: 20, AR060: 17, AR282: 14, AR300: 14, AR283: 11, AR240: 11, AR277: 10, H0040: 17, H0251: 14, L0758: 10, L0748: 8, L0731: 8, H0494: 7, L0666: 7, H0144: 7, H0659: 7, L0747: 7, L0749: 7, L0757: 7, H0038: 6, H0529: 6, L0770: 6, L0662: 6, L0659: 6, H0013: 5, H0318: 5, H0616: 5, S0440: 5, L0775: 5, L0776: 5, H0519: 5, L0588: 5, L0592: 5, H0341: 4, S0360: 4, H0412: 4, L0663: 4, H0547: 4, L0754: 4, L0595: 4, H0542: 4, H0543: 4, H0423: 4, H0171: 3, H0657: 3, H0656: 3, S0045: 3, L3388: 3, H0581: 3, S0049: 3, T0110: 3, H0046: 3, H0090: 3, H0591: 3, H0551: 3, H0100: 3, H0022: 3, H0625: 3, H0633: 3, S0422: 3, L0375: 3, L0664: 3, H0682: 3, S0406: 3, L0740: 3, H0556: 2, H0241: 2, H0638: 2, S0418: 2, L0005: 2, S0442: 2, S0376: 2, H0722: 2, H0393: 2, L0717: 2, S0222: 2, H0574: 2, H0486: 2, T0040: 2, L0471: 2, S0051: 2, S0003: 2, H0252: 2, L0483: 2, T0006: 2, H0031: 2, H0032: 2, H0124: 2, H0634: 2, H0264: 2, T0042: 2, S0150: 2, H0646: 2, L0763: 2, L0637: 2, L0646: 2, L0374: 2, L0764: 2, L0768: 2, L0653: 2, L0665: 2, H0593: 2, H0435: 2, H0658: 2, H0539: 2, S0152: 2, L3832: 2, H0521: 2, S3014: 2, S0027: 2, S0028: 2, L0439: 2, L0750: 2, L0777: 2, S0436: 2, L0596: 2, L0608: 2, L0604: 2, L0594: 2, L0362: 2, S0026: 2, H0667: 2, S0452: 2, H0506: 2, L0411: 1, H0624: 1, H0170: 1, H0395: 1, H0265: 1, T0002: 1, H0220: 1, H0140: 1, H0159: 1, H0686: 1, H0583: 1, H0650: 1, S0212: 1, H0484: 1, H0664: 1, L0481: 1, S0356: 1, S0354: 1, S0358: 1, S0444: 1, S0408: 1, L3649: 1, H0580: 1, H0747: 1, H0437: 1, H0431: 1, T0104: 1, H0600: 1, H0592: 1, H0586: 1, L3817: 1, H0642: 1, H0632: 1, L2482: 1, T0114: 1, H0244: 1, H0250: 1, H0069: 1, H0156: 1, L0021: 1, H0599: 1, H0036: 1, S0346: 1, H0596: 1, H0544: 1, H0009: 1, N0006: 1, L0157: 1, H0569: 1, H0123: 1, H0242: 1, H0024: 1, H0083: 1, H0375: 1, H0328: 1, H0615: 1, H0428: 1, H0039: 1, H0622: 1, H0213: 1, H0553: 1, L0142: 1, H0628: 1, H0674: 1, H0388: 1, L0456: 1, H0708: 1, H0068: 1, H0598: 1, S0036: 1, H0135: 1, H0087: 1, H0380: 1, H0413: 1, H0056: 1, L0351: 1, T0041: 1, H0334: 1, H0561: 1, H0366: 1, S0448: 1, S0294: 1, H0130: 1, H0641: 1, H0649: 1, S0208: 1, S0002: 1, S0426: 1, L0520: 1, L0631: 1, L0769: 1, L0638: 1, L5565: 1, L0667: 1, L0772: 1, L0372: 1, L0641: 1, L0626: 1, L0794: 1, L0766: 1, L0381: 1, L0650: 1, L0651: 1, L0806: 1, L0655: 1, L0807: 1, L0657: 1, L0636: 1, L0518: 1, L0782: 1, L0382: 1, L0809: 1, L3391: 1, L2263: 1, L2259: 1, L2262: 1, L0565: 1, H0693: 1, L3827: 1, H0520: 1, S0126: 1, H0689: 1, H0670: 1, H0660: 1, H0666: 1, H0648: 1, L0602: 1, H0710: 1, H0518: 1, S0176: 1, H0134: 1, H0555: 1, H0436: 1, H0478: 1, H0631: 1, L0779: 1, L0752: 1, S0434: 1, L0605: 1, L0591: 1, L0599: 1, H0665: 1, S0196: 1, L2368: 1, H0008: 1 and H0352: 1. 221 HTWEH94 561680 231 AR313: 9, AR039: 7, AR096: 5, AR300: 3, AR185: 3, AR089: 3, AR299: 3, AR277: 2, AR316: 2, AR240: 2, AR060: 2, AR104: 2, AR218: 1, AR282: 1, AR055: 1, L0766: 1 and H0436: 1. 222 HTXDG92 658730 232 AR218: 44, AR277: 37, AR283: 37, AR219: 35, AR055: 31, AR316: 30, AR089: 29, AR104: 23, AR299: 21, AR240: 20, AR313: 20, AR039: 19, AR282: 19, AR185: 19, AR096: 18, AR060: 17, AR300: 17, L0777: 11, H0618: 7, L0438: 6, H0144: 5, L0758: 5, S0410: 4, H0059: 4, L0601: 4, H0556: 3, H0253: 3, H0052: 3, H0620: 3, H0617: 3, L0764: 3, L0768: 3, L0744: 3, L0747: 3, H0265: 2, H0341: 2, S0046: 2, S0222: 2, H0013: 2, H0069: 2, S0049: 2, H0150: 2, H0087: 2, L0351: 2, L0771: 2, L0766: 2, L0665: 2, H0547: 2, H0659: 2, L0748: 2, L0439: 2, L0754: 2, L0749: 2, H0542: 2, L3643: 1, S0040: 1, H0717: 1, H0716: 1, S0114: 1, T0049: 1, H0583: 1, H0657: 1, H0656: 1, H0381: 1, H0663: 1, S0358: 1, H0734: 1, S0007: 1, H0747: 1, S0278: 1, H0261: 1, H0550: 1, H0392: 1, H0486: 1, T0114: 1, S0010: 1, H0581: 1, H0374: 1, H0327: 1, H0545: 1, H0457: 1, H0012: 1, H0024: 1, H0015: 1, H0510: 1, H0594: 1, H0188: 1, H0292: 1, H0286: 1, H0622: 1, H0181: 1, H0135: 1, H0040: 1, H0063: 1, H0100: 1, T0041: 1, H0561: 1, S0440: 1, H0509: 1, H0529: 1, L0640: 1, L0770: 1, L0769: 1, L3905: 1, L5566: 1, L0773: 1, L0662: 1, L0363: 1, L0774: 1, L0775: 1, L0806: 1, L0559: 1, L0783: 1, L0383: 1, L5623: 1, H0698: 1, S0374: 1, H0520: 1, H0519: 1, S0292: 1, S0126: 1, H0682: 1, S0380: 1, H0696: 1, S0027: 1, L0740: 1, L0731: 1, H0445: 1, L0605: 1, L0592: 1 and H0543: 1. 223 HTXET11 581521 233 AR240: 7, AR055: 6, AR060: 5, AR283: 5, AR282: 5, AR300: 4, AR218: 4, AR277: 4, AR089: 3, AR185: 3, AR104: 3, AR039: 3, AR096: 3, AR316: 3, AR313: 2, AR299: 2, AR219: 2, H0265: 1 and S0442: 1. 224 HTXFA72 853410 234 AR313: 47, AR039: 45, AR299: 26, AR089: 23, AR096: 23, AR185: 22, AR300: 20, AR277: 19, AR219: 17, AR316: 16, AR240: 14, AR104: 14, AR060: 12, AR218: 11, AR282: 10, AR055: 8, AR283: 5, H0265: 1 225 HTXJD85 840391 235 AR313: 38, AR039: 32, AR096: 17, AR185: 17, AR300: 17, AR277: 16, AR299: 15, AR089: 15, AR240: 12, AR316: 10, AR219: 10, AR104: 9, AR060: 8, AR055: 8, AR218: 8, AR282: 6, AR283: 4, H0556: 2, L0638: 1, L0748: 1 and L0439: 1. 226 HTXJY08 637774 236 AR055: 2, AR060: 2, AR300: 2, AR299: 2, AR313: 2, AR185: 1, AR282: 1, AR089: 1, AR039: 1, AR316: 1, AR219: 1, H0556: 1, S0442: 1, H0036: 1, H0590: 1, H0024: 1, H0100: 1, L0769: 1, L0667: 1, L0438: 1, L0740: 1 and L0777: 1. 227 HTXLT36 843477 237 AR218: 8, AR240: 7, AR313: 7, AR060: 7, AR055: 7, AR089: 6, AR096: 6, AR104: 6, AR185: 6, AR299: 6, AR316: 5, AR300: 5, AR219: 5, AR039: 5, AR282: 5, AR277: 3, AR283: 3, H0250: 2, H0477: 2, L0804: 2, L0791: 2, H0660: 2, S0406: 2, L0758: 2, H0171: 1, H0556: 1, H0713: 1, H0717: 1, T0049: 1, L0760: 1, S0356: 1, H0747: 1, H0587: 1, L3653: 1, H0013: 1, H0635: 1, H0081: 1, S0003: 1, H0135: 1, H0090: 1, T0042: 1, L0065: 1, S0440: 1, S0422: 1, L0520: 1, L0766: 1, L0655: 1, L4501: 1, L0665: 1, H0539: 1, L0747: 1, L0749: 1, L0757: 1, L0759: 1, H0423: 1, H0422: 1 and H0352: 1. 228 HUFCL31 801938 238 AR060: 26, AR240: 10, AR300: 9, AR096: 9, AR316: 8, AR299: 8, AR089: 8, AR218: 7, AR313: 5, AR219: 5, AR283: 5, AR055: 4, AR039: 4, AR104: 4, AR185: 3, AR282: 3, AR277: 2, L0764: 5, L0771: 5, H0506: 4, L0374: 3, S0434: 3, S0356: 1, S0410: 1, H0264: 1, L0372: 1, L0783: 1, L0532: 1 and L0663: 1. 229 HUKDF20 566823 239 AR055: 7, AR218: 6, AR060: 6, AR300: 5, AR282: 4, AR104: 4, AR313: 4, AR283: 4, AR185: 4, AR299: 4, AR277: 3, AR219: 3, AR089: 3, AR316: 3, AR039: 3, AR240: 3, AR096: 2, H0261: 1, H0266: 1 and H0059: 1. 230 HUSCJ14 894699 240 AR239: 10, AR228: 10, AR227: 9, AR237: 9, AR230: 8, AR233: 8, AR287: 8, AR203: 7, AR288: 7, AR176: 6, AR184: 6, AR199: 6, AR229: 6, AR215: 6, AR190: 6, AR200: 5, AR245: 5, AR174: 5, AR234: 5, AR191: 5, AR180: 4, AR297: 4, AR232: 4, AR226: 4, AR289: 4, AR298: 4, AR194: 4, AR170: 4, AR257: 4, AR061: 3, AR292: 3, AR173: 3, AR231: 3, AR262: 3, AR242: 3, AR284: 3, AR286: 3, AR251: 3, AR179: 3, AR236: 3, AR238: 3, AR255: 3, AR161: 3, AR189: 3, AR162: 3, AR235: 3, AR293: 3, AR282: 3, AR188: 3, AR294: 3, AR165: 3, AR163: 3, AR164: 3, AR166: 3, AR285: 2, AR201: 2, AR181: 2, AR295: 2, AR177: 2, AR247: 2, AR290: 2, AR205: 2, AR300: 2, AR225: 2, AR260: 2, AR198: 2, AR261: 2, AR193: 2, AR291: 2, AR268: 2, AR175: 2, AR270: 2, AR183: 2, AR211: 2, AR296: 2, AR196: 2, AR185: 2, AR258: 2, AR250: 2, AR240: 2, AR178: 2, AR204: 2, AR195: 2, AR060: 2, AR312: 1, AR311: 1, AR210: 1, AR224: 1, AR243: 1, AR299: 1, AR269: 1, AR316: 1, AR275: 1, AR186: 1, AR172: 1, AR039: 1, AR267: 1, AR256: 1, AR263: 1, AR055: 1, AR089: 1, AR217: 1, L2654: 6, L0741: 4, S0192: 4, H0677: 4, H0556: 3, H0013: 3, H0052: 3, L0766: 3, L0744: 3, L0439: 3, L0757: 3, H0265: 2, S0040: 2, S0410: 2, H0599: 2, H0545: 2, H0266: 2, H0030: 2, H0135: 2, L3905: 2, L5622: 2, H0520: 2, H0547: 2, H0519: 2, L0748: 2, L0756: 2, L0777: 2, L0780: 2, L0758: 2, L0485: 2, L0604: 2, H0739: 1, H0713: 1, S0134: 1, S0218: 1, H0656: 1, L2909: 1, S0212: 1, H0663: 1, S0420: 1, L1562: 1, S0360: 1, S0408: 1, H0742: 1, S0132: 1, S0476: 1, H0393: 1, H0587: 1, T0040: 1, H0575: 1, H0309: 1, H0009: 1, L0471: 1, H0620: 1, H0510: 1, H0290: 1, S0250: 1, S0022: 1, T0023: 1, H0488: 1, H0268: 1, T0041: 1, T0042: 1, H0538: 1, S0210: 1, L0763: 1, L0800: 1, L0771: 1, L0794: 1, L0804: 1, L0774: 1, L0775: 1, L5623: 1, L0793: 1, L2652: 1, L2257: 1, L2260: 1, L0710: 1, L2262: 1, H0144: 1, H0593: 1, H0435: 1, H0521: 1, H0555: 1, L0743: 1, L0754: 1, L0779: 1, L0752: 1, S0031: 1, S0436: 1, L0596: 1, L0605: 1, L0601: 1, S0106: 1, H0667: 1, S0276: 1 and L3576: 1. 231 HUVDJ48 564853 241 AR055: 6, AR060: 5, AR283: 5, AR039: 5, AR185: 4, AR096: 4, AR240: 4, AR104: 4, AR299: 4, AR300: 3, AR089: 3, AR316: 3, AR313: 3, AR282: 3, AR218: 2, AR277: 2, AR219: 2, H0393: 1, H0056: 1 and L0662: 1. 232 HWBBU75 780360 242 L0665: 4, H0457: 3, H0264: 3, L0766: 3, H0521: 3, L0745: 3, H0556: 2, H0580: 2, S0352: 2, L0761: 2, L0806: 2, L0789: 2, L0748: 2, H0542: 2, H0255: 1, S0278: 1, H0581: 1, H0271: 1, H0719: 1, H0413: 1, H0494: 1, S0002: 1, S0426: 1, L0769: 1, L0774: 1, H0660: 1, L0750: 1, L0752: 1, L0753: 1 and S0424: 1. 233 HWBCN36 722259 243 AR104: 3, AR185: 3, AR039: 2, AR055: 2, AR282: 2, AR300: 2, AR060: 1, AR096: 1, AR089: 1, AR240: 1, AR277: 1, AR316: 1 H0580: 1 234 HWBDJ08 762860 244 AR313: 31, AR039: 30, AR096: 19, AR218: 18, AR316: 17, AR300: 17, AR219: 16, AR299: 13, AR185: 12, AR277: 12, AR089: 12, AR104: 8, AR240: 7, AR060: 5, AR282: 5, AR055: 4, AR283: 1, L0794: 7, H0556: 4, S0414: 4, L0779: 4, H0031: 3, S0216: 3, H0265: 2, H0220: 2, H0688: 2, H0634: 2, L0655: 2, L0665: 2, H0659: 2, S0328: 2, H0521: 2, L0753: 2, L0758: 2, H0422: 2, S0114: 1, H0300: 1, S0356: 1, S0360: 1, H0580: 1, S0046: 1, H0643: 1, L3655: 1, H0250: 1, H0069: 1, H0635: 1, H0042: 1, H0575: 1, H0581: 1, S0049: 1, L0045: 1, H0622: 1, H0644: 1, H0641: 1, S0002: 1, L0763: 1, L0653: 1, L0776: 1, L0793: 1, L0777: 1, L0755: 1, L0731: 1, L0593: 1 and H0542: 1. 235 HWLBO67 834315 245 S0374: 1 236 HWLGP26 834770 246 AR313: 10, AR039: 7, AR096: 6, AR316: 5, AR299: 4, AR240: 4, AR300: 3, AR277: 3, AR089: 3, AR060: 2, AR185: 2, AR282: 2, AR055: 2, AR218: 1, AR283: 1, L0766: 5, L0803: 5, L0794: 3, S0410: 2, H0551: 2, H0435: 2, L0756: 2, L0731: 2, H0585: 1, S0212: 1, S0282: 1, L0534: 1, S0442: 1, S0354: 1, H0735: 1, H0486: 1, H0014: 1, H0354: 1, H0644: 1, H0135: 1, H0647: 1, L0369: 1, L0640: 1, L0763: 1, L0770: 1, L3905: 1, L0646: 1, L0771: 1, L0804: 1, L0784: 1, L0528: 1, L0789: 1, L0790: 1, L0792: 1, L3827: 1, H0658: 1, L0749: 1, L0758: 1 and S0436: 1. 237 HILCA24 869856 247 AR316: 4, AR282: 2, AR096: 1, AR299: 1, AR039: 1, L0748: 4, H0090: 2, L0659: 2, H0521: 2, L0777: 2, L0608: 2, H0543: 2, T0002: 1, S0114: 1, L3658: 1, S0358: 1, S0408: 1, L3649: 1, T0109: 1, H0581: 1, H0622: 1, H0031: 1, H0644: 1, S0002: 1, L0657: 1, L0526: 1, L0789: 1, L0664: 1, S0380: 1, H0522: 1, L0749: 1 and L0779: 1. HILCA24 782450 260 238 HYABC84 865064 248 AR313: 19, AR219: 16, AR218: 13, AR104: 13, AR096: 11, AR316: 11, AR240: 10, AR299: 10, AR089: 10, AR282: 9, AR185: 9, AR039: 9, AR283: 8, AR277: 7, AR060: 6, AR055: 5, AR300: 5 HYABC84 789854 261 239 HPWTF23 844775 249 AR240: 84, AR089: 51, AR299: 38, AR096: 37, AR039: 36, AR313: 34, AR185: 24, AR300: 22, AR316: 22, AR282: 19, AR283: 15, AR104: 14, AR055: 10, AR060: 10, AR277: 6, AR218: 2, S0474: 47, H0710: 28, L0747: 18, L0659: 17, H0656: 13, H0436: 10, H0271: 9, L0751: 9, H0581: 8, H0179: 8, H0063: 8, L0731: 8, L0599: 8, H0740: 7, L0756: 7, H0650: 6, L0662: 6, H0555: 6, S0354: 5, H0728: 5, H0733: 5, H0734: 5, H0036: 5, H0590: 5, H0052: 5, L0770: 5, S0428: 5, S0374: 5, L0439: 5, L3643: 4, H0717: 4, H0747: 4, H0393: 4, S0222: 4, H0156: 4, H0309: 4, S0312: 4, S0314: 4, H0090: 4, H0591: 4, L0637: 4, L0761: 4, L0776: 4, L0783: 4, L0438: 4, L0757: 4, H0543: 4, H0716: 3, H0662: 3, H0402: 3, H0619: 3, H0392: 3, H0575: 3, H0004: 3, H0673: 3, S0364: 3, H0135: 3, H0059: 3, H0494: 3, L0667: 3, L0764: 3, L0803: 3, L0775: 3, L0666: 3, L3811: 3, H0670: 3, L0744: 3, L0750: 3, L0779: 3, L0758: 3, L0759: 3, S0436: 3, H0556: 2, L3644: 2, H0713: 2, S6024: 2, H0341: 2, S0282: 2, S0442: 2, S0376: 2, S0360: 2, H0580: 2, H0329: 2, H0749: 2, H0645: 2, H0369: 2, H0486: 2, S0280: 2, H0042: 2, H0421: 2, H0545: 2, H0457: 2, H0620: 2, H0014: 2, S0051: 2, T0010: 2, S0340: 2, H0031: 2, H0644: 2, H0383: 2, H0674: 2, H0551: 2, H0264: 2, H0488: 2, T0004: 2, S0438: 2, H0130: 2, H0647: 2, S0422: 2, L0766: 2, L0655: 2, L0517: 2, L0518: 2, L0809: 2, L0647: 2, H0547: 2, H0660: 2, S0044: 2, S0027: 2, S0028: 2, L0748: 2, L0754: 2, L0745: 2, H0445: 2, S0434: 2, L0596: 2, L0588: 2, H0506: 2, H0170: 1, S0134: 1, L0414: 1, L0785: 1, S0212: 1, H0255: 1, S0358: 1, S0444: 1, L3649: 1, H0637: 1, H0729: 1, H0730: 1, H0741: 1, H0208: 1, S6022: 1, H0550: 1, H0609: 1, H0586: 1, H0333: 1, T0060: 1, H0427: 1, L0021: 1, L0022: 1, S0010: 1, S0346: 1, L0105: 1, H0318: 1, H0597: 1, H0150: 1, L0471: 1, H0011: 1, S0362: 1, H0373: 1, S0388: 1, H0354: 1, H0099: 1, H0594: 1, H0266: 1, H0416: 1, H0188: 1, S0318: 1, S0334: 1, H0687: 1, S0338: 1, H0252: 1, H0213: 1, H0553: 1, H0111: 1, H0617: 1, H0169: 1, H0163: 1, T0067: 1, L0435: 1, L0564: 1, S0440: 1, H0509: 1, S0150: 1, H0646: 1, H0652: 1, L3815: 1, L0371: 1, L0769: 1, L0771: 1, L0649: 1, L0774: 1, L0375: 1, L0651: 1, L0378: 1, L0805: 1, L0606: 1, L0657: 1, L0384: 1, L0529: 1, L5623: 1, L0793: 1, L0664: 1, S0216: 1, H0144: 1, H0723: 1, H0593: 1, H0689: 1, H0659: 1, H0672: 1, S0328: 1, H0539: 1, H0518: 1, H0521: 1, H0696: 1, H0134: 1, L0612: 1, H0732: 1, S3012: 1, S0390: 1, S0037: 1, S3014: 1, S0032: 1, L0743: 1, L0749: 1, L0752: 1, L0755: 1, H0707: 1, L0591: 1, L0592: 1, H0653: 1, H0136: 1, S0412: 1 and H0721: 1. HPWTF23 843700 262 240 HLWAU42 695737 250 AR055: 57, AR060: 56, AR185: 55, AR299: 45, AR283: 43, AR089: 41, AR282: 37, AR104: 35, AR316: 31, AR300: 25, AR039: 24, AR096: 23, AR240: 22, AR313: 22, AR277: 22, AR218: 16, AR219: 9, L0740: 8, H0486: 5, L0439: 5, H0733: 4, L0606: 4, L0731: 4, H0553: 3, S0422: 3, H0672: 3, H0696: 3, L0747: 3, H0581: 2, H0428: 2, H0169: 2, L0774: 2, L0518: 2, L0438: 2, H0436: 2, L0744: 2, L0779: 2, L0752: 2, S0436: 2, L0362: 2, S0242: 2, S0412: 2, S0040: 1, H0713: 1, H0656: 1, H0341: 1, H0661: 1, H0459: 1, S0444: 1, S0360: 1, H0729: 1, H0728: 1, H0734: 1, L0717: 1, H0411: 1, S0278: 1, H0431: 1, H0592: 1, H0587: 1, H0331: 1, H0013: 1, H0156: 1, H0599: 1, L0105: 1, H0015: 1, H0051: 1, H0355: 1, S0022: 1, H0030: 1, H0031: 1, H0032: 1, S0440: 1, H0509: 1, H0132: 1, H0646: 1, S0210: 1, L0770: 1, L3905: 1, L0766: 1, L0775: 1, L0661: 1, L0783: 1, L0666: 1, L0664: 1, L0665: 1, H0723: 1, H0724: 1, H0648: 1, S0330: 1, S0044: 1, S0028: 1, L0743: 1, L0756: 1, L0755: 1, L0759: 1, H0595: 1, S0192: 1, S0276: 1, S0196: 1 and H0423: 1. HLWAU42 840855 263 241 HGCAC19 851527 251 AR219: 2, AR316: 2, AR096: 1, L0794: 15, L0803: 12, L0766: 7, H0013: 6, H0090: 6, L0663: 6, L0777: 6, L0731: 6, L0759: 6, H0457: 5, H0328: 5, L0493: 5, L0666: 5, L0754: 5, L0749: 5, H0543: 5, H0656: 4, S0358: 4, H0615: 4, L0665: 4, H0521: 4, L0779: 4, L0588: 4, H0305: 3, S0360: 3, H0036: 3, H0052: 3, T0042: 3, L0761: 3, L0805: 3, L0809: 3, H0144: 3, H0670: 3, H0696: 3, L0591: 3, S0134: 2, H0657: 2, L3659: 2, S0418: 2, S0442: 2, S0007: 2, S0045: 2, L0717: 2, H0600: 2, H0486: 2, H0156: 2, H0575: 2, H0590: 2, H0024: 2, S0022: 2, L0483: 2, H0135: 2, H0038: 2, H0560: 2, S0422: 2, L0457: 2, H0529: 2, L0625: 2, L0648: 2, L0776: 2, L0655: 2, L0527: 2, S0374: 2, H0520: 2, H0519: 2, H0659: 2, H0436: 2, L0748: 2, L0745: 2, L0581: 2, L0361: 2, H0542: 2, H0423: 2, S0424: 2, H0624: 1, H0171: 1, H0556: 1, T0002: 1, H0686: 1, S0342: 1, H0717: 1, T0049: 1, S0430: 1, H0650: 1, H0341: 1, H0663: 1, H0589: 1, S0356: 1, S0376: 1, S0408: 1, S0410: 1, L2336: 1, H0329: 1, S0046: 1, H0645: 1, H0369: 1, S6014: 1, H0370: 1, H0455: 1, H0438: 1, H0602: 1, H0586: 1, H0587: 1, H0574: 1, H0559: 1, S0280: 1, L0021: 1, H0318: 1, S0474: 1, H0263: 1, T0115: 1, H0545: 1, L0157: 1, H0123: 1, L0471: 1, H0015: 1, S0388: 1, S0051: 1, H0375: 1, H0271: 1, H0188: 1, S0312: 1, S0003: 1, H0688: 1, H0039: 1, H0622: 1, H0031: 1, H0644: 1, L0055: 1, H0169: 1, L0456: 1, H0163: 1, H0634: 1, H0551: 1, H0379: 1, H0488: 1, H0279: 1, L0475: 1, S0352: 1, H0652: 1, S0208: 1, L0640: 1, L0763: 1, L0500: 1, L0769: 1, L0646: 1, L0662: 1, L0649: 1, L0498: 1, L0804: 1, L0650: 1, L0784: 1, L0806: 1, L0653: 1, L0606: 1, L0515: 1, L0659: 1, L0526: 1, L0519: 1, L0788: 1, L0790: 1, L0791: 1, L0664: 1, S0053: 1, S0296: 1, H0547: 1, S0126: 1, H0682: 1, H0684: 1, H0658: 1, H0660: 1, H0672: 1, S0380: 1, H0518: 1, H0525: 1, S0044: 1, S0404: 1, S0406: 1, H0479: 1, S0432: 1, S3014: 1, L0744: 1, L0750: 1, L0780: 1, L0753: 1, L0604: 1, S0106: 1, S0242: 1, S0196: 1, S0452: 1 and H0506: 1. HGCAC19 842540 264 HGCAC19 801999 265 242 HEQBJ01 876546 252 AR277: 12, AR283: 11, AR219: 11, AR316: 10, AR089: 10, AR218: 9, AR104: 9, AR055: 8, AR282: 8, AR313: 8, AR096: 7, AR300: 7, AR185: 7, AR299: 7, AR240: 7, AR060: 5, AR039: 5, S0360: 3, H0619: 3, H0673: 2, L0438: 2, H0685: 1, S0444: 1, H0544: 1, H0266: 1, H0163: 1, L0770: 1, L0646: 1, L0768: 1, L0766: 1, L0803: 1, L0776: 1, S0152: 1, S0027: 1, L0439: 1, L0747: 1, L0777: 1, L0752: 1 and L0758: 1. HEQBJ01 861786 266 HEQBJ01 834633 267 243 HBJHT01 587262 253 AR313: 10, AR039: 8, AR299: 6, AR300: 5, AR185: 5, AR055: 5, AR277: 5, AR060: 4, AR096: 4, AR089: 4, AR316: 4, AR240: 3, AR104: 3, AR282: 2, AR218: 2, AR283: 2, L0667: 2, S0114: 1, H0351: 1, H0318: 1, H0615: 1 and L0764: 1. HBJHT01 580026 268 244 HE8FD92 901142 254 AR055: 6, AR299: 6, AR060: 6, AR240: 5, AR218: 5, AR219: 5, AR300: 5, AR185: 5, AR089: 4, AR316: 3, AR096: 3, AR104: 3, AR039: 3, AR277: 3, AR283: 2, AR282: 2, AR313: 2 HE8FD92 888274 269 HE8FD92 869847 270 HE8FD92 856544 271 HE8FD92 843825 272 245 HBDAB91 864374 255 AR282: 3, AR219: 1, H0551: 2, L0803: 2, L0439: 2, L0750: 2, S0308: 2, L0644: 1, L0655: 1, L0809: 1, L0780: 1 and L0752: 1. HBDAB91 789532 273

Table 1C summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID:), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ ID NO:B). The first column provides a unique clone identifier, “Clone ID:”, for a cDNA clone related to each contig sequence. The second column provides the sequence identifier, “SEQ ID NO:X”, for each contig sequence. The third column provides a unique contig identifier, “Contig ID:” for each contig sequence. The fourth column, provides a BAC identifier “BAC ID NO:A” for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, “SEQ ID NO:B” for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, “Exon From-To”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof). TABLE 1C cDNA SEQ ID CONTIG BAC SEQ ID EXON Clone ID NO: X ID: ID: A NO: B From-To H6EEU40 12 757048 AC026285 537  1-414  440-1918 H6EEU40 12 757048 AC023920 538  1-416  44-1920 H6EEU40 12 757048 AC026285 539   1-1458 1729-1836 H6EEU40 12 757048 AC023920 540   1-1459 1730-1837 HACBJ56 13 847112 AC069497 541  1-117 2470-3367 4908-5262 5641-5756 7886-8200  9815-11138 HACBJ56 13 847112 AC007104 542  1-802 2342-2695 3074-3189 5319-5633 7248-8571 HACBJ56 13 847112 AC069497 543  1-453 HACBJ56 13 847112 AC007104 544  1-453 HACBS22 14 847113 AC012073 545  1-134 718-833 1002-1132 2357-2516 3762-3945 5344-5477 7446-7594 7742-7904 10636-10725 11138-12223 12583-12977 13095-13178 14224-14532 14668-14841 15779-16124 16257-16343 16508-16826 17489-17757 17847-18008 19028-19192 19755-23561 24286-24717 24920-25347 25567-25741 26629-26891 27895-27968 HACBS22 14 847113 AC012073 546  1-545 HADMA77 17 783049 AC007944 547   1-3350 HADMA77 17 783049 AC018656 548   1-3349 HADMA77 17 783049 AC021874 549   1-3351 4529-4959 6110-6438 HADMA77 17 783049 AC007944 550  1-941 HADMA77 17 783049 AC018656 551  1-432 HADMA77 17 783049 AC018656 552  1-941 HADMB15 18 847116 AC026666 553  1-385 406-780 HADMB15 18 847116 AC026281 554  1-114 430-875  896-1262 HAGFJ67 21 861680 AL353805 555   1-1465 HAGFJ67 21 861680 AL354917 556   1-1465 HAGFJ67 21 861680 AL353793 557   1-1464 HAGFJ67 21 861680 AL353805 558  1-565 HAGFJ67 21 861680 AL353793 559  1-565 HAGFS57 22 847120 AC021238 560  1-140 3343-3636 5052-5179 5712-5796 6486-6918 7867-8404 8934-9513  9711-10538 10984-11992 12080-12349 12485-12857 13895-14212 14994-15054 15169-15297 16132-16211 17721-17811 18135-18354 18363-18444 19661-19720 19841-20784 20920-21236 22168-24079 HAGFS57 22 847120 AC066613 561  1-433 1382-1919 2449-3028 3226-4053 4499-5507 5595-5864 6000-6372 7410-7727 8509-8569 8684-8812 9647-9726 11236-11326 11650-11869 11878-11959 13176-13235 13356-14299 14435-14752 15684-17595 HAGHR18 24 655435 AC009671 562   1-1134 HAJAY92 26 845601 AL353726 563   1-2332 HAJAY92 26 845601 AL353726 564  1-115 HAJAY92 26 845601 AL353726 565  1-115 HARAE26 29 560598 AC024491 566   1-1237 HATCD80 30 826098 AL158801 567   1-1974 HATCD80 30 826098 AL158801 568  1-90 HBAGD86 31 838799 AC016755 569  1-41 1648-1993 2035-3552 3554-6713 HBAGD86 31 838799 AC016755 570  1-161 696-809 2256-2753 6910-6991 7733-7857 9267-9458 10650-10734 11114-11562 11678-11801 12524-12817 14494-15914 HBAGD86 31 838799 AC016755 571  1-217 HBHAA05 33 603174 AL353743 572  1-677 HBHAA05 33 603174 AL161453 573  1-677 HBHAA05 33 603174 AL161453 574  1-339 HBHAA81 34 846465 AC006059 575  1-230 1619-1699 1953-2090 2986-3054 3665-3786 3902-4406 4457-4674 5129-5531 5660-5811 5934-5969 7563-7959 8086-9195 9591-9735  9788-10149 HBHAA81 34 846465 AC018471 576  1-230 1619-1699 1965-2090 2986-3054 3665-3786 3902-4405 4456-4673 5128-5530 5659-5810 5933-5968 7561-7957 8084-9193 9589-9733  9786-10146 HBHAA81 34 846465 AC006059 577  1-340 501-802 HBHAA81 34 846465 AC006059 578  1-661 1538-1684 3489-3680 3832-3933 4241-4410 5782-5872 5998-6150 HBHAA81 34 846465 AC018471 579  1-661 1539-1672 HBHAA81 34 846465 AC018471 580  1-340 501-802 HBJAB02 35 837309 AC015651 581  1-35 159-252 410-783 786-830  953-1035 1452-1553 1651-2071 2161-2264 2352-2454 2494-2758 2847-3006 3135-3272 3477-4138 4907-5738 5972-6059 6132-6367 6650-6834 6915-7010 7091-7658 7662-9457 10122-10222 11415-11534 12386-12418 13253-13584 13635-13867 14881-15326 15851-16013 16529-16816 17430-17529 18140-18269 18634-18734 19189-19369 20434-21105 21912-22008 HBJAB02 35 837309 AC015651 582   1-2097 5308-5495 5696-5742 5890-6249 7370-7525 7850-8236 8359-8463 8597-8770 8919-9028 9213-9353 9517-9639 9765-9874  9944-11023 11124-11219 11315-11613 11708-12241 12431-12666 12744-12802 12976-13087 13374-13914 14728-15500 HBJAC40 36 841235 AC007606 583  1-89 520-616 811-972 1604-1874 1982-5038 5125-5260 6459-6956 7370-7473 7507-7774 8952-9321 HBJAC40 36 841235 AC007606 584  1-403  428-1236 HBJDW56 38 520401 AC005532 585  1-626 HBJDW56 38 520401 AC005532 586  1-516 HBJDW56 38 520401 AC005532 587  1-176 HBXCM66 44 639039 AC011962 588  1-102 HCEEE79 48 560609 AC006923 589   1-1044 HCEEE79 48 560609 AC006923 590  1-207 HCEFG93 49 745400 AC068128 591   1-2635 HCEFG93 49 745400 AC011140 592   1-2636 HCFLN88 51 610000 AC005089 593  1-594 1779-2065 2224-2411 3295-3588 3962-4463 5317-5561 5835-6210 6750-7793 HCFLN88 51 610000 AC005089 594  1-141 HCFLN88 51 610000 AC005089 595  1-215 HCLBK61 53 845659 AC009299 596   1-1756 HCLBK61 53 845659 AC009299 597  1-359 HCMSX51 54 788643 U96629 598   1-3014 HCMSX51 54 788643 AC040975 599   1-3014 HCNCO11 55 775086 AC011319 600  1-700 HCNCO11 55 775086 AC069204 601  1-700 HCNCO11 55 775086 AC011319 602  1-354 HCNCO11 55 775086 AC011319 603  1-338 HCNCO11 55 775086 AC069204 604  1-354 HCQBH72 57 637548 AC073530 605   1-1790 HCQBH72 57 637548 AC073530 606  1-106 HCQBH72 57 637548 AC073530 607  1-410 HCWAE64 60 535893 AL157935 608   1-1319 2024-2316 2937-2984 3126-3281 5595-5703 5788-6574 6667-6733 6788-6880 6962-7303  8111-11869 12019-12418 12420-12679 13140-13191 HCWAE64 60 535893 AL157935 609   1-1316 HCWAE64 60 535893 AL157935 610  1-309 HDPDI72 62 897277 AL139238 611  1-76 3170-3542 4724-5613 6598-6719 6954-7373 8256-8349 10408-11003 HDPDI72 62 897277 AL139238 612  1-279 HDPIY31 66 886159 AL356790 613  1-114  949-1189 2041-2318 2541-2711 2797-2871 3152-7720 HDPIY31 66 886159 AL118506 614  1-241 1067-1317 1567-1737 1823-1897 2178-6746 HDPIY31 66 886159 AL356790 615  1-104 116-297 HDPIY31 66 886159 AL356790 616  1-481 HDPIY31 66 886159 AL118506 617  1-89 HDPPQ30 69 684292 AL022315 618  1-968 HDPPQ30 69 684292 AL022315 619  1-255 HDTLM18 71 836057 AL049843 620  1-148  811-1104 2196-2793 2930-2991 3921-4047 6575-6627 8124-8659 8741-8843 9448-9886 10480-10524 10944-11103 13917-14450 14801-15344 16392-17295 18110-18311 20445-21421 21596-22268 23857-23968 24205-24585 24623-24701 25168-25575 28078-28391 28548-28707 29039-29839 30732-31495 32024-32487 32521-33216 34511-34647 35166-35720 36527-36797 36993-37125 38178-38288 39341-39646 41511-41570 42307-42873 42914-43014 43248-43465 43589-43690 43724-43909 44170-44333 44517-45130 45497-45961 46215-46842 47926-48126 49391-51961 HDTLM18 71 836057 AL049843 621   1-2071 HDTLM18 71 836057 AL049843 622  1-76 2590-2720 4185-4370 7052-7178 7385-7428 HE2CM39 72 553651 AC018391 623   1-3570 3779-3904 4646-5979 6339-6701 6710-8473 HE2CM39 72 553651 AC018391 624  1-438 HE2CM39 72 553651 AC018391 625   1-1402 1586-1871 2685-2797 3088-3503 4900-5170 5789-5882 6089-6195 HE6FU11 74 827236 AL021578 626  1-116 2674-2776 3489-4063 7279-7402  9706-10120 10217-10368 12042-12219 12315-12924 14271-14380 14463-14842 16153-16301 HE6FV29 75 588454 AL162401 627   1-1425 HE8BQ49 76 589443 AC009225 628   1-1857 HB8SG96 77 862016 AL138707 629  1-152  684-1297 1697-3720 4478-6193 HE8SG96 77 862016 AL138707 630  1-336 HEBCI18 81 831464 AC013399 631   1-3602 HEBCI18 81 831464 AC013399 632  1-651 HEBDQ91 83 840288 AC008623 633   1-2883 HEBDQ91 83 840288 AC008623 634  1-350 HEBDQ91 83 840288 AC008623 635  1-555 HEBFR46 84 847064 AC006483 636  1-70 282-644  789-4243 HEBFR46 84 847064 AC073481 637   1-2167 2174-3461 HEBFR46 84 847064 AC006483 638  1-344 HEBFR46 84 847064 AC006483 639  1-195 HEBGE07 85 798096 AC021918 640   1-1899 HEBGE07 85 798096 AC021918 641  1-225 HEBGE23 86 836129 AC006486 642  1-976 1287-1533 1631-1785 1868-2476 2517-3500 HEBGE23 86 836129 AC021858 643  1-632 HEBGE23 86 836129 AC006486 644  1-174 HEBGE23 86 836129 AC006486 645  1-509 539-830 1796-2057 2096-2262 2409-2658 2862-3403 4612-4900 4910-5022 5115-5768 7511-7738 8302-8392 9165-9436 10716-11025 12552-13090 13282-13789 HEGAU15 87 834379 AC009404 646   1-1121 HEGAU15 87 834379 AC011638 647   1-1119 HEGAU15 87 834379 AC009404 648  1-363 HEGAU15 87 834379 AC009404 649  1-446 HEGAU15 87 834379 AC011638 650  1-446 HEGAU15 87 834379 AC011638 651  1-363 HFCEI04 88 692438 AC068996 652  1-865 HFCEI04 88 692438 AC068303 653  1-865 HFEAY59 89 658685 AC005919 654  1-490  976-1063 1264-1351 1663-1956 2076-2238 2674-2837 2910-3034 4517-4686 4804-5021 5234-5282 5397-5729 7103-7442 HFEAY59 89 658685 AC005919 655  1-155 HFIJA68 91 847074 AC010550 656  1-127 HFKFX64 93 566835 AP001203 657  1-870 HFKFX64 93 566835 AC025291 658  1-868 HFKFX64 93 566835 AC010798 659  1-868 HFKFX64 93 566835 AP001203 660  1-750 HFKFX64 93 566835 AC025291 661  1-750 HFKFX64 93 566835 AC010798 662  1-750 HFTAS49 95 847386 AC025405 663  1-89 1179-1585 1793-1888 2057-2469 2682-3084 3387-4038 4507-6765  6791-13862 HFTAS49 95 847386 AL354740 664  1-47 245-499 2148-2236 3326-3732 3940-4035 4204-4616 4829-5231 5536-6187 6656-8914  8941-13186 HFTAS49 95 847386 AL354740 665  1-187 HFVHW43 96 570948 AL132795 666  1-253 1142-1455 1576-2150 2529-2966 4374-4471 4991-5361 6514-7738 7936-8053 9858-9979 11930-12101 12401-12525 12531-12712 16593-16786 17053-17214 18919-19396 21174-21327 21724-22296 22515-23071 HFVHW43 96 570948 AL132795 667   1-6181 HFVHW43 96 570948 AL132795 668  1-287 622-861 HGBER72 97 826710 AL157935 669   1-1319 2024-2316 2937-2984 3126-3281 5595-5703 5788-6574 6667-6733 6788-6880 6962-7303  8111-11869 12019-12418 12420-12679 13140-13191 HGBER72 97 826710 AL157935 670   1-1316 HGBER72 97 826710 AL157935 671  1-309 HGBHP91 98 693011 AL356056 672   1-1048 HGBHP91 98 693011 AL136982 673   1-1048 HGBHP91 98 693011 AL356056 674  1-238 HGBHP91 98 693011 AL356056 675  1-135 HGBHP91 98 693011 AL136982 676  1-238 HGBHP91 98 693011 AL136982 677  1-136 HGLBG15 99 701990 AC005082 678  1-252 2150-2418 2461-2695 2700-3101 3368-3776 6066-6250 7105-7363 8329-9740 HGLBG15 99 701990 AC073992 679  1-259 1225-2636 HGLBG15 99 701990 AC005082 680  1-546 HGLBG15 99 701990 AC073992 681  1-282 HHEAK45 100 765278 AL035690 682   1-2148 4277-4419 5252-5365 5452-6322 6863-7710 HHEAK45 100 765278 AC010388 683   1-2149 HHEAK45 100 765278 AL035690 684  1-732 HHEAK45 100 765278 AL035690 685  1-86 175-566 HHFEB79 102 1300768 AC022305 686  1-686 HHFEB79 102 1300768 AL022167 687   1-1796 HHFEB79 102 1300768 AL049186 688  1-912 HHFEB79 102 1300768 AC068470 689  1-706 HHFEB79 102 1300768 AC018903 690  1-631 HHFEB79 102 1300768 AL049186 691  1-87 HHFEC39 103 609873 AL022726 692  1-819 1137-4813 HHFEC39 103 609873 AL022726 693  1-509 HHFFS40 104 824059 AC022423 694   1-2017 HHFFS40 104 824059 AC025178 695   1-2017 HHFFS40 104 824059 AC022444 696   1-2017 HHPFU28 107 824573 AC069200 697   1-2595 HHPFU28 107 824573 AC069200 698   1-3998 HHPFU28 107 824573 AC069200 699  1-777 HHSBI06 108 639097 AF285442 700   1-1170 1250-1439 1565-1850 2214-2632 HHSBI06 108 639097 AF271897 701   1-1174 1253-1444 1568-1853 2217-2659 4394-4876 5269-6156 7228-8366 8574-8852 HHSBI06 108 639097 AC025857 702   1-1172 1254-1442 1566-1851 2215-2618 4423-4905 5298-6179 7253-8391 8599-8877 HHSBI06 108 639097 AF285442 703  1-483 HHSBI06 108 639097 AF285442 704  1-323 420-676 774-935 1372-1637 HHSBI06 108 639097 AF271897 705  1-522 HHSBI06 108 639097 AF271897 706  1-323 420-676 774-935 1372-1637 HHSBI06 108 639097 AC025857 707  1-522 HHSBI06 108 639097 AC025857 708  1-323 420-676 774-935 1372-1637 HHSBI65 109 801910 AF205589 709   1-1703 1798-2217 2302-3089 HHSBI65 109 801910 AF205589 710  1-531  571-1759 1862-2104 2219-2722 HISAT67 110 843549 AC013403 711  1-753  852-1545 1734-1816 1930-2061 2259-2428 2573-2648 2685-2987 3135-4126 4242-4543 4732-4905 5033-5145 5298-5341 5530-5715 6059-6126 HISAT67 110 843549 AC013403 712  1-102 HISBA38 111 561711 AL137020 713   1-1169 HISBA38 111 561711 AL359254 714   1-1169 HISBA38 111 561711 AL137020 715  1-702 HISBA38 111 561711 AL359254 716  1-702 HJPCH08 114 840365 AC004826 717  1-71 475-867 2289-2390 2475-2596 3191-3333 3458-3644 3729-3859 4038-4233 4338-4451 4558-4626 4832-4977 5108-5272 5380-5622 5698-5816 5965-6067 6380-6580 6829-6920 7162-7299  7943-10018 10503-10623 10699-10776 10917-11336 12343-12406 12731-13275 HJPCH08 114 840365 AC004826 718  1-406  862-1119 1423-1689 2886-2989 5361-5431 5969-6059 6874-7181 9823-9980 10928-11194 12667-12838 17063-18165 18168-18649 18785-19579 19733-19780 20247-20355 21063-21415 21546-22630 23320-23541 24276-24323 24510-24602 24903-25357 26015-27115 27309-28272 28601-28879 29413-29552 30539-30602 30728-31110 31231-31353 32257-32325 33895-34173 35081-35392 37763-37860 38789-38822 38920-39119 HJPCH08 114 840365 AC004826 719  1-424 2065-2241 HKIXC44 116 716213 AC016240 720  1-195 476-552 679-763 1040-1119 1998-3764 HKIXC44 116 716213 AF261720 721  1-195 475-551 678-762 1039-1118 1998-3764 HKIXC44 116 716213 AC016240 722  1-423 HKIXC44 116 716213 AF261720 723  1-423 HKIXC44 116 716213 AF261720 724  1-206 HKTAB41 117 695732 AC006451 725  1-737 HLDBG17 118 855953 AL161798 726   1-1403 HLHAP05 120 638476 AC009097 727  1-101 HLHBS54 121 837503 AL020996 728  1-122  973-1079 3003-3636 3733-4238 5772-5955 7540-7752 7989-8112 8643-8783 10417-10491 10647-10842 11649-11762 11922-12346 12667-12760 12832-12954 13035-13141 13358-13818 14508-17386 18605-18733 HLHBS54 121 837503 AL020996 729  1-73 275-708  893-1047 1096-1399 1619-2003 2288-2518 2565-3369 3500-3687 3690-3794 4245-4515 4967-5882 6346-6458 6648-6872 7729-8095 9551-9877 10983-11246 11967-12988 HLHCS23 122 560663 AL356385 730   1-1419 HLHCS23 122 560663 AC016501 731   1-1419 HLHCS23 122 560663 AL356385 732  1-560 HLHCS23 122 560663 AC016501 733  1-560 HLYAR30 125 781249 AC018391 734   1-3570 3779-3904 4646-5979 6339-6701 6710-8473 HLYAR30 125 781249 AC018391 735  1-438 HLYAR30 125 781249 AC018391 736   1-1402 1586-1871 2685-2797 3088-3503 4900-5170 5789-5882 6089-6195 HLYDF73 126 566869 AL122127 737  1-583 HMDAB29 129 584789 AC027264 738  1-147 HMDAB29 129 584789 AC068682 739  1-153 HMDAB29 129 584789 AL354887 740   1-1433 HMDAB29 129 584789 AL157408 741   1-1434 HMDAB29 129 584789 AL354887 742  1-577 HMDAB29 129 584789 AL354887 743  1-196 HMDAB29 129 584789 AL157408 744  1-577 HMDAB29 129 584789 AL157408 745  1-196 HMDAD44 130 566854 AC012370 746  1-145 2813-4454 HMDAD44 130 566854 AC034121 747   1-1569 HMDAD44 130 566854 AC012370 748  1-787 HMDAD44 130 566854 AC012370 749  1-622 HMEDE24 131 837027 AC011078 750  1-297 359-416 3247-3653 6083-6236  9753-10036 11128-11233 12148-12514 12635-13141 15604-16463 19071-19190 19476-20232 20321-20638 21200-21594 21959-22219 23120-23362 23467-24143 24766-24853 25725-26143 26310-26455 27545-30619 30708-31169 HMIBD93 133 634227 AC010913 751   1-3640 HMIBD93 133 634227 AC010913 752  1-495 593-668  670-1055 1578-1799 2445-2717 3103-3203 3284-3751 3841-4032 5093-5261 5443-5872 5922-6838 7633-8170 8304-8491 8968-9029  9888-10020 10479-10733 10807-10958 11020-11132 12080-12373 12464-12585 13223-13381 17379-17471 18572-19447 HMIBF07 134 603528 AC022833 753   1-1721 HMQAI38 136 589964 AC000403 754  1-32 225-465 3716-3779 3917-4243 5065-5157 6778-6987 7684-7829  8473-10115 HMQAI38 136 589964 AL136440 755  1-64 202-528 1350-1439 3073-3276 3973-4099 4762-6404 HMWBL03 140 822861 AC012052 756  1-130 548-784 4520-4887 5112-6285 6741-6888 7577-7727 7951-8582  8927-10292 HMWBL03 140 822861 AC011667 757  1-138 1281-1681 2270-2632 3070-3372 3865-3990 4407-4644 8378-8745  8970-10143 10599-10746 11435-11585 11809-12440 12785-14150 HMWBL03 140 822861 AC012052 758  1-303 HNECW49 142 639117 AC011864 759  1-522 HNECW49 142 639117 AC011864 760  1-607 HNECW49 142 639117 AC011864 761  1-741 HNFGR08 144 825417 AC006369 762   1-1423 HNGAK51 145 603910 AC013443 763  1-913 HNGAK51 145 603910 AC013443 764  1-406 HNGAK51 145 603910 AC013443 765  1-297 HNGDX18 146 1145071 AL391069 766   1-1403 HNGDX18 146 1145071 AL158846 767  1-193 208-577 894-1167 1401-1629 1918-3320 4039-4082  9400-10337 HNGDX18 146 1145071 AL391069 768  1-274 HNGDX18 146 1145071 AL158846 769  1-117 HNGFR54 147 695748 AC007316 770  1-456 HNGFR54 147 695748 AC007316 771  1-260 HNGHK37 149 609889 AC023177 772   1-1532 HNGJB41 151 852178 AC004542 773  1-108 192-278 349-470 678-804 2945-4433 4687-4749 5583-5951 6304-6501 7398-7867 10583-10956 11008-11440 11603-11875 12070-12473 HNGJB41 151 852178 AC004542 774  1-976 HNGKT41 152 836061 AC008581 775   1-1099 HNGNO53 154 836063 AC023387 776  1-869 HNGNO53 154 836063 AL355500 777  1-851 HNGPJ25 155 834942 AP002781 778   1-1472 HNHCT47 156 634691 AC027793 779  1-147 HNHCT47 156 634691 AC022107 780  1-111 HNHCT47 156 634691 AP001271 781  1-610 HNHCT47 156 634691 AP000487 782  1-610 HNHCT47 156 634691 AP000405 783  1-612 HNHCT47 156 634691 AP001271 784  1-375 HNHCT47 156 634691 AP000487 785  1-36 434-873 HNHCT47 156 634691 AP000405 786  1-375 HNHKV56 158 800877 AC009396 787   1-1605 HODBB70 160 520196 AC006322 788  1-561 HODBB70 160 520196 AC073110 789  1-561 HODBB70 160 520196 AC025553 790  1-561 HODBB70 160 520196 AC006322 791   1-1741 HODBB70 160 520196 AC006322 792  1-354 HODBB70 160 520196 AC073110 793   1-1741 HODBB70 160 520196 AC073110 794  1-354 HORBS82 165 638293 AL034419 795   1-1798 HORBS82 165 638293 AL034419 796   1-1186 HOUDE92 169 580866 AC005865 797  1-173 553-629 1941-2042 2757-2891 3294-3378 4606-5498 5550-8125 HPCAL26 170 762822 AP000654 798   1-4150 HPEBA84 172 753957 AL357372 799   1-1238 HPEBA84 172 753957 AL161799 800   1-1112 HPEBA84 172 753957 AL357372 801  1-294 HPEBA84 172 753957 AL357372 802  1-140 HPEBA84 172 753957 AL161799 803  1-294 HPFCI36 173 855966 AL161652 804  1-174  313-4710 HPFDI37 174 862056 AC000090 805  1-29 566-712 1355-1425 3075-3241 3725-3806 4295-4357 5382-5571 6510-7016 7981-8321 HPJCW58 176 612866 AC024735 806   1-1160 HPMCV30 177 612870 AC006512 807  1-658 3090-3543 4479-5105 5885-6846 7103-9707  9914-10293 11523-12034 12067-12181 13769-14031 14199-14291 14584-14790 15123-15154 17039-17482 17539-17987 18697-19052 19112-19380 20023-20268 21158-21598 21817-22221 23565-23665 23906-24076 24981-25506 25510-25861 25981-26645 26661-27449 27717-27812 27991-28024 28437-28888 29651-33442 33621-34089 34245-34808 34819-35284 35854-35960 38525-38771 HPMCV30 177 612870 AC005517 808  1-945 HPMCV30 177 612870 AC006512 809  1-315 439-531  707-1080 1144-1227 1491-1845 2113-2321 2700-3556 3818-4307 4336-4813 4958-5775 HPMCV30 177 612870 AC006512 810  1-738 HPMCV30 177 612870 AC005517 811  1-352 HPMCV30 177 612870 AC005517 812  1-177 HPRCM72 180 813512 AC015867 813  1-291  634-3334 HPRCM72 180 813512 AC010189 814   1-3040 3384-6081 HPRCM72 180 813512 AC015867 815  1-305 HPRCM72 180 813512 AC010189 816  1-740 HPRCM72 180 813512 AC010189 817  1-305 HPTRI42 182 655362 AC004229 818  1-98 1759-1841 2062-2504 2787-2818 2897-2984 3079-3168 3423-3593 3666-3786 4178-4301 4459-4598 5581-5689 5784-5890 6035-6068 6179-6267 6672-7873 HPTRI42 182 655362 AC019071 819  1-136 1023-1365 2131-2213 2434-2875 3158-3189 3268-3355 3450-3539 3794-3964 4037-4157 4549-4672 4830-4969 5952-6060 6155-6261 6406-6439 6549-6637 7041-8091 HPTRI42 182 655362 AC004229 820   1-2392 2959-3254 HPTRQ52 184 655363 AC021462 821  1-763  771-1244 HPTRQ52 184 655363 AC068629 822  1-916 HPTRQ52 184 655363 AL355514 823  1-265  397-1368 1377-1655 2338-3396 HPTRQ52 184 655363 AC021462 824  1-187 HPTRQ52 184 655363 AC021462 825  1-975 HPWBA29 186 561956 AL160011 826  1-318 HPWBA29 186 561956 AL160011 827  1-568  736-1212 HRDAI17 187 560720 AL139385 828  1-99 HRDAI17 187 560720 AC008439 829  1-125 HRDAI17 187 560720 AC034240 830  1-141 HRDAI17 187 560720 AC015884 831  1-207 HRDAI17 187 560720 AC008690 832  1-164 HRDAI17 187 560720 AC022032 833  1-146 HRDAI17 187 560720 AC027802 834  1-117 HRDAI17 187 560720 AC060763 835  1-129 HRDAI17 187 560720 AC073842 836  1-165 HRDAI17 187 560720 AC023018 837  1-145 HRDAI17 187 560720 AC021163 838  1-97  402-2108 2292-2943 2997-3408 3423-3481 3551-4145 4557-5026 5029-6260 6276-6930 6936-7000 HRDAI17 187 560720 AC068013 839  1-125 HRDAI17 187 560720 AC023398 840  1-134 HRDAI17 187 560720 AC015884 841  1-131 HRDDQ39 188 840405 AC009152 842  1-755 HSAVW42 191 637660 AC021117 843  1-865 HSAVW42 191 637660 AC021117 844  1-336 397-651 HSAVW42 191 637660 AC021117 845  1-185 HSAWZ40 193 634000 AC024249 846   1-1532 HSAWZ40 193 634000 AC024249 847  1-409 HSAWZ40 193 634000 AC024249 848  1-319 HSDBI90 195 853376 AC010285 849  1-731 1367-3915 4065-5062 HSDBI90 195 853376 AC008393 850  1-730  961-1358 1366-3914 4064-5061 HSDBI90 195 853376 AC010313 851  1-731  962-1359 1367-3916 4066-5063 HSDBI90 195 853376 AC010285 852  1-133 HSDBI90 195 853376 AC010285 853  1-282 HSDBI90 195 853376 AC008393 854  1-133 HSDBI90 195 853376 AC010313 855  1-246 HSDBI90 195 853376 AC010313 856  1-115 HSHAX04 196 812178 AL049824 857  1-110 1211-1257 1740-1878 3062-3144 3668-3772 4775-5175 5220-5345 7001-7384 8361-8657 8747-8937 9876-9980 12753-12901 13131-13891 14272-14726 14851-16619 16683-17910 18078-18367 HSHAX04 196 812178 AL354888 858  1-47 1277-1376 2477-2523 3006-3144 4326-4408 4932-5036 6039-6439 6484-6609 8265-8648 9625-9921 10011-10216 11141-11245 14019-14167 14397-15157 15538-15992 16117-17885 17949-19176 19344-19633 HSHAX04 196 812178 AL354888 859  1-314 HSHAX04 196 812178 AL354888 860  1-599 HSKDR27 197 580874 AC008742 861  1-50 1016-1321 1979-2220 2313-3310 HSKDR27 197 580874 AC008742 862  1-495 HSRFD18 199 840771 AL096819 863   1-3975 HSRFD18 199 840771 AL096819 864  1-304 HSSEF77 200 658725 AC005041 865  1-68  87-493 711-838  997-1167 2227-2960 3326-4641 4768-5786 HSSEF77 200 658725 AC005041 866   1-2920 3439-3667 3839-4332 HSSEF77 200 658725 AC005041 867  1-143 HSSGJ58 201 747714 AL355491 868   1-1936 HSSGJ58 201 747714 AL356112 869   1-1936 HSSGJ58 201 747714 AL354665 870   1-1932 HSVBD37 202 637110 AL359554 871  1-125 340-404 1268-1408 1655-1862 2328-2417 4005-4354 5438-6584 HSVBD37 202 637110 AL354940 872  1-145 155-344 1428-2582 HSVBD37 202 637110 AL157708 873  1-145 155-344 1428-2579 HSVBD37 202 637110 AL359554 874   1-1191 1690-2151 2730-2963 3372-3513 3977-4114 HSVBD37 202 637110 AL359554 875  1-240 HSVBD37 202 637110 AL354940 876   1-1115 HSVBD37 202 637110 AL157708 877   1-1115 HSYBI06 203 740766 AL049795 878  1-135 2267-2358 2759-2859 3659-3775 4814-4946 5270-5730 6026-6474 6782-7341 7359-7475 7777-7939 8137-8247 8262-8548 8649-8729  9467-10551 10640-10701 11022-11356 11406-11450 11517-11645 12002-12057 12580-12713 14863-15041 15151-15479 16120-21982 HSYBI06 203 740766 AL049795 879  1-98 HSYBI06 203 740766 AL049795 880  1-110 HT4FV41 204 853400 AC011547 881  1-170 793-936 2771-3041 3691-3788 5141-5252 5755-6030 6325-6407 7214-7551 8653-8940 9033-9136 9428-9907 11266-11659 12082-12263 13451-13544 13664-13699 13769-13936 14571-14761 14897-14997 15135-17127 HT4FV41 204 853400 AC005331 882  1-88 224-324  462-2454 HT4FV41 204 853400 AC023470 883  1-80 204-242 313-477 1213-1300 1436-1536 1673-3658 HT4FV41 204 853400 AC005331 884  1-607 HT4FV41 204 853400 AC023470 885  1-606 HTEDJ28 209 762845 AC025974 886   1-2357 HTEDJ28 209 762845 AC013370 887   1-2357 HTEHU59 210 840385 AP001003 888   1-3207 HTEHU59 210 840385 AP001557 889   1-3206 HTEHU59 210 840385 AP001156 890   1-3207 HTEHU59 210 840385 AP001003 891  1-863 HTEHU59 210 840385 AP001003 892   1-1399 1504-1948 1956-2672 2761-2905 3007-3135 3290-3445 3537-3653 3746-3913 4010-4131 4251-4428 HTEHU59 210 840385 AP001557 893  1-863 HTEHU59 210 840385 AP001557 894   1-1395 1500-1944 1952-2667 2757-2900 3002-3130 3285-3439 HTEHU59 210 840385 AP001156 895   1-1396 1502-1945 1953-2668 HTEHU59 210 840385 AP001156 896  1-863 HTEJD29 211 695798 AL354733 897   1-1292 HTEJD29 211 695798 AC007943 898   1-1292 HTEJD29 211 695798 AL354733 899  1-184 HTEJD29 211 695798 AL354733 900  1-59 1212-1284 1905-1956 2351-2840 4126-5105 5892-6298 6726-7122 7204-7713 7747-7932 HTHBZ06 216 832477 AC068768 901  1-835 HTLBT80 217 840045 AL133227 902  1-51 476-521  842-1226 1375-1490 3745-4016 4046-4229 4430-4855 5300-6053 6598-6883 7406-7446 7461-8437 8550-8681 8888-8919 8943-9353 9458-9544  9834-10607 11550-11629 12196-12374 13532-14886 HTLBT80 217 840045 AL133227 903  1-32  712-1071 3453-3870 4197-4326 4639-4751 5131-5202 5588-5638 7454-8108 8670-8767 9511-9692  9754-10134 11109-11226 12456-12607 15237-15316 18143-18311 18429-18478 20682-20982 20988-21295 22686-23061 23358-23495 24076-24612 25196-25334 26760-26926 27041-27152 27271-27379 27697-28289 29024-29340 29761-29840 31168-32681 HTLCX82 218 847091 AC004471 904  1-478 1424-1734 1764-1994 2027-2127 2589-2825 4635-4805 4929-5050 5134-5289 5367-5501 6339-6446 6780-6902 7225-7337 9237-9728 10180-10725 11846-13361 HTLCX82 218 847091 AC004471 905  1-919 HTLDU78 219 637702 AC011444 906   1-1305 HTLDU78 219 637702 AC011444 907  1-285 HTLDU78 219 637702 AC011444 908  1-274 HTLEV48 220 723799 AL079300 909  1-833 1783-2055 2908-3362 3583-4048 HTLEV48 220 723799 AL079300 910  1-163 HTLFA13 221 535937 AC022007 911   1-1127 HTLFA13 221 535937 AC021995 912   1-1115 HTLFA13 221 535937 AC007783 913   1-1144 HTLFA13 221 535937 AC022007 914   1-1729 HTLFA13 221 535937 AC022007 915  1-179 184-696 HTLFA13 221 535937 AC021995 916  1-106 132-190 674-831 1456-1588 3423-4270 4811-4933 5118-5304 HTLFA13 221 535937 AC021995 917  1-179 184-696 894-945 HTLFA13 221 535937 AC007783 918  1-169 180-258 681-859  864-1376 3240-3503 HTLFA13 221 535937 AC007783 919   1-1729 HTLGI89 222 835069 AC048342 920  1-130 HTLGI89 222 835069 AC009453 921  1-143 HTLGI89 222 835069 AC022231 922  1-151 HTLGI89 222 835069 AC009524 923  1-151 HTLGI89 222 835069 AC048342 924  1-118 HTOAM11 224 664508 AC002369 925  1-586 2559-2651 3329-3426 3756-5088 HTOAM11 224 664508 AP001486 926   1-1191 HTOAM11 224 664508 AP000875 927   1-1192 HTOAM11 224 664508 AC002369 928  1-228 HTOAM11 224 664508 AP001486 929  1-711 HTOAM11 224 664508 AP001486 930  1-374 HTOAM11 224 664508 AP000875 931  1-710 HTODH83 225 580884 AC012046 932   1-1972 HTODH83 225 580884 AC012046 933  1-105 HTTEE41 230 840950 AC018921 934  1-92 318-578 837-912 1091-1249 1321-1387 1862-2192 2485-2579 2708-2831 3685-4257 4547-5127 5811-6037 6562-7076 7541-7678 8069-8191 10100-10207 11102-11688 11721-11847 12201-12335 12532-12641 12888-12991 13027-13546 13637-16146 HTTEE41 230 840950 AC018921 935  1-100 HTWEH94 231 561680 AC004858 936   1-1349 1370-1744 HTWEH94 231 561680 AC004858 937  1-94 HTWEH94 231 561680 AC004858 938  1-199 HTXET11 233 581521 AC011802 939  1-984 HTXET11 233 581521 AC025414 940  1-984 HTXET11 233 581521 AC011802 941  1-36 836-964 4059-5438 6005-6176 6789-7120 7124-7588 7735-7827 7925-8770 9057-9545 HTXET11 233 581521 AC025414 942  1-36 836-964 4059-5438 6002-6173 6786-7117 7121-7585 7732-7809 HTXFA72 234 853410 AP001812 943   1-1015 HTXFA72 234 853410 AP000822 944   1-1015 HTXFA72 234 853410 AP001812 945  1-130 HTXFA72 234 853410 AP000822 946  1-527 HTXJD85 235 840391 AC078797 947   1-1239 HTXJD85 235 840391 AC078797 948   1-2296 2428-2719 HTXJD85 235 840391 AC078797 949  1-224 HTXJY08 236 637774 AC005962 950   1-2075 HTXJY08 236 637774 AC004757 951   1-2075 HTXJY08 236 637774 AC005962 952  1-478 HTXJY08 236 637774 AC005962 953   1-1011 HTXJY08 236 637774 AC004757 954  1-478 HTXJY08 236 637774 AC004757 955   1-1011 HTXLT36 237 843477 AC006160 956  1-175 3693-4007 5248-5429 6946-7065 7636-8072  8959-10995 HTXLT36 237 843477 AC006160 957  1-461 1144-1986 HTXLT36 237 843477 AC006160 958  1-81 185-259 314-593 HUFCL31 238 801938 AC012255 959  1-417  834-1753 1788-1918 2176-2628 2755-2971 3036-5033 HUFCL31 238 801938 AC012255 960  1-134 HUSCJ14 240 894699 AC007040 961  1-149 394-889 1061-1139 2097-2249 2852-3007 5021-5089 5217-5919 6119-8896 HUSCJ14 240 894699 AC007040 962  1-854 HUSCJ14 240 894699 AC007040 963  1-397 HWBCN36 243 722259 AL031296 964  1-670 1590-2584 3609-3751 4204-4803 4847-5271  9874-10146 11847-12328 12493-13051 13395-13635 15455-15917 17288-17739 18945-19908 21414-22006 27737-27823 35955-36575 36643-37204 37341-37504 39154-39312 41736-42263 47221-47669 47712-48167 50898-51095 51163-51655 51716-52580 52706-58181 HWBCN36 243 722259 AL109757 965  1-670 1590-2583 3578-3751 4203-4802 HWBCN36 243 722259 AL031296 966  1-274 HWBCN36 243 722259 AL109757 967  1-425 HWBDJ08 244 762860 AL133351 968  1-238 2679-2860 6204-6544 6911-7399 7795-7909 8430-8914 9187-9620  9744-10234 11159-11190 11310-11737 12408-16037 HWBDJ08 244 762860 AC013339 969  1-238 2699-2880 6224-6564 6931-7419 7815-7929 8449-8932 9205-9638  9762-10130 10144-10309 11380-11807 12478-16107 HWBDJ08 244 762860 AL133351 970  1-466 HWBDJ08 244 762860 AC013339 971  1-466 HWLBO67 245 834315 AC011739 972  1-517 HWLBO67 245 834315 AC011739 973  1-586 3120-3867 4726-4866 6044-6395 6686-7156 11614-12016 18205-18501 HWLBO67 245 834315 AC011739 974  1-202 HYABC84 248 865064 AL132825 975   1-2512 2604-2740 2974-3241   1-2512 2604-2740 2974-3241 HYABC84 248 865064 AL132825 976  1-553  1-553 1059-1263 1059-1263 3121-3476 3121-3476 5284-5734 5284-5734 6284-6513 6284-6513 6786-7426 6786-7426 8674-8733 8674-8733 10656-10933 10656-10933 11453-11555 11453-11555 12991-13079 12991-13079 13839-14281 13839-14281 14527-14827 14527-14827 15156-15685 15156-15685 15835-16046 15835-16046 16166-16604 16166-16604 16736-19566 16736-19566 19658-19794 19658-19794 20028-20295 20028-20295 HYABC84 248 865064 AL132825 977  1-188  1-188 HLWAU42 250 695737 AC010794 978   1-3291   1-3291 HLWAU42 250 695737 AC009985 979   1-3291   1-3291 HLWAU42 250 695737 AC010794 980  1-92  1-92 HLWAU42 250 695737 AC010794 981  1-279  1-279 736-997 736-997 1377-1619 1377-1619 3065-3511 3065-3511 3829-7852 3829-7852 HLWAU42 250 695737 AC009985 982  1-279 736-997 1320-1633 3065-3511 3829-7851  1-279 736-997 1320-1633 3065-3511 3829-7851 HEQBJ01 252 876546 AC009079 983  1-198 1263-1467 2271-2369 5035-5870 5888-6174 6249-6472  7148-11343  1-198 1263-1467 2271-2369 5035-5870 5888-6174 6249-6472  7148-11343 HEQBJ01 252 876546 AC009079 984  1-173 916-970  1-173 916-970 HF8FD92 254 901142 AL359176 985   1-2410   1-2410   1-2410 2420-4226 2420-4226 2420-4226 HE8FD92 254 901142 AL139152 986  1-826  863-2063 2125-4935 4945-6753  1-826  863-2063 2125-4935 4945-6753  1-826  863-2063 2125-4935 4945-6753  1-826  863-2063 2125-4935 4945-6753 HE8FD92 254 901142 AL109937 987  1-168 233-930 1572-1748 2463-3391 HE8FD92 254 901142 AC027209 988   1-1201   1-1201   1-1201 1263-1531 1263-1531 1263-1531 1648-5860 1648-5860 1648-5860 HE8FD92 254 901142 AL356004 989   1-1052 1062-2871 HE8FD92 254 901142 AL139152 990  1-560  760-1714 1740-3644 3736-4319 4872-4998  1-560  760-1714 1740-3644 3736-4319 4872-4998  1-560  760-1714 1740-3644 3736-4319 4872-4998  1-560  760-1714 1740-3644 3736-4319 4872-4998 HE8FD92 254 901142 AL109937 991  1-437 HE8FD92 254 901142 AC027209 992  1-560  1-560  1-560  747-1721  747-1721  747-1721 1875-3650 1875-3650 1875-3650 3698-4325 3698-4325 3698-4325 4657-4693 4657-4693 4657-4693 4879-5008 4879-5008 4879-5008 HE8FD92 254 901142 AC027209 993  1-423  1-423  1-423 HE8FD92 254 901142 AL356004 994  1-560

Table 1D: The polynucleotides or polypeptides, or agonists or antagonists of the present invention can be used in assays to test for one or more biological activities. If these polynucleotides and polypeptides do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity. Thus, the polynucleotides or polypeptides, or agonists or antagonists could be used to treat the associated disease.

The present invention encompasses methods of detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating a disease or disorder. In preferred embodiments, the present invention encompasses a method of treating a hematopoietic and hematologic diseases and disorders comprising administering to a patient in which such detection, treatment, prevention, and/or amelioration is desired a protein, nucleic acid, or antibody of the invention (or fragment or variant thereof) in an amount effective to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate the hematopoietic and hematologic diseases and disorder.

In another embodiment, the present invention also encompasses methods of detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating a hematopoietic and hematologic diseases and disorder; comprising administering to a patient combinations of the proteins, nucleic acids, or antibodies of the invention (or fragments or variants thereof), sharing similar indications as shown in the corresponding rows in Column 3 of Table 1D.

Table 1D provides information related to biological activities for polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof). Table 1D also provides information related to assays which may be used to test polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof) for the corresponding biological activities. The first column (“Gene No.”) provides the gene number in the application for each clone identifier. The second column (“cDNA Clone ID:”) provides the unique clone identifier for each clone as previously described and indicated in Table 1A through Table 1D. The third column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ ID Number for polypeptide sequences encoded by the corresponding cDNA clones (also as indicated in Tables 1A, Table 1B, and Table 2). The fourth column (“Biological Activity”) indicates a biological activity corresponding to the indicated polypeptides (or polynucleotides encoding said polypeptides). The fifth column (“Exemplary Activity Assay”) further describes the corresponding biological activity and also provides information pertaining to the various types of assays which may be performed to test, demonstrate, or quantify the corresponding biological activity.

Table 1D describes the use of, inter alia, FMAT technology for testing or demonstrating various biological activities. Fluorometric microvolume assay technology (FMAT) is a fluorescence-based system which provides a means to perform nonradioactive cell- and bead-based assays to detect activation of cell signal transduction pathways. This technology was designed specifically for ligand binding and immunological assays. Using this technology, fluorescent cells or beads at the bottom of the well are detected as localized areas of concentrated fluorescence using a data processing system. Unbound flurophore comprising the background signal is ignored, allowing for a wide variety of homogeneous assays. FMAT technology may be used for peptide ligand binding assays, immunofluorescence, apoptosis, cytotoxicity, and bead-based immunocapture assays. See, Miraglia S et. al., “Homogeneous cell and bead based assays for highthroughput screening using flourometric microvolume assay technology,” Journal of Biomolecular Screening; 4:193-204 (1999). In particular, FMAT technology may be used to test, confirm, and/or identify the ability of polypeptides (including polypeptide fragments and variants) to activate signal transduction pathways. For example, FMAT technology may be used to test, confirm, and/or identify the ability of polypeptides to upregulate production of immunomodulatory proteins (such as, for example, interleukins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as other cellular regulators (e.g. insulin)).

Table 1D also describes the use of kinase assays for testing, demonstrating, or quantifying biological activity. In this regard, the phosphorylation and de-phosphorylation of specific amino acid residues (e.g. Tyrosine, Serine, Threonine) on cell-signal transduction proteins provides a fast, reversible means for activation and de-activation of cellular signal transduction pathways. Moreover, cell signal transduction via phosphorylation/de-phosphorylation is crucial to the regulation of a wide variety of cellular processes (e.g. proliferation, differentiation, migration, apoptosis, etc.). Accordingly, kinase assays provide a powerful tool useful for testing, confirming, and/or identifying polypeptides (including polypeptide fragments and variants) that mediate cell signal transduction events via protein phosphorylation. See e.g., Forrer, P., Tamaskovic R., and Jaussi, R. “Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and p38 Kinase Activities” Biol. Chem. 379(8-9): 1101-1110 (1998). LENGTHY TABLE REFERENCED HERE US20070026454A1-20070201-T00001 Please refer to the end of the specification for access instructions.

Table 2 further characterizes certain encoded polypeptides of the invention, by providing the results of comparisons to protein and protein family databases. The first column provides a unique clone identifier, “Clone ID NO:”, corresponding to a cDNA clone disclosed in Table 1A and/or Table 1B. The second column provides the unique contig identifier, “Contig ID:” which allows correlation with the information in Table 1B. The third column provides the sequence identifier, “SEQ ID NO:”, for the contig polynucleotide sequences. The fourth column provides the analysis method by which the homology/identity disclosed in the Table was determined. The fifth column provides a description of the PFAM/NR hit identified by each analysis. Column six provides the accession number of the PFAM/NR hit disclosed in the fifth column. Column seven, score/percent identity, provides a quality score or the percent identity, of the hit disclosed in column five. Comparisons were made between polypeptides encoded by polynucleotides of the invention and a non-redundant protein database (herein referred to as “NR”), or a database of protein families (herein referred to as “PFAM”), as described below.

The NR database, which comprises the NBRF PIR database, the NCBI GenPept database, and the SIB SwissProt and TrEMBL databases, was made non-redundant using the computer program nrdb2 (Warren Gish, Washington University in Saint Louis). Each of the polynucleotides shown in Table 1B, column 3 (e.g., SEQ ID NO:X or the ‘Query’ sequence) was used to search against the NR database. The computer program BLASTX was used to compare a 6-frame translation of the Query sequence to the NR database (for information about the BLASTX algorithm please see Altshul et al., J. Mol. Biol. 215:403-410 (1990), and Gish and States, Nat. Genet. 3:266-272 (1993). A description of the sequence that is most similar to the Query sequence (the highest scoring ‘Subject’) is shown in column five of Table 2 and the database accession number for that sequence is provided in column six. The highest scoring ‘Subject’ is reported in Table 2 if (a) the estimated probability that the match occurred by chance alone is less than 1.0 e-07, and (b) the match was not to a known repetitive element. BLASTX returns alignments of short polypeptide segments of the Query and Subject sequences which share a high degree of similarity; these segments are known as High-Scoring Segment Pairs or HSPs. Table 2 reports the degree of similarity between the Query and the Subject for each HSP as a percent identity in Column 7. The percent identity is determined by dividing the number of exact matches between the two aligned sequences in the HSP, dividing by the number of Query amino acids in the HSP and multiplying by 100. The polynucleotides of SEQ ID NO:X which encode the polypeptide sequence that generates an HSP are delineated by columns 8 and 9 of Table 2.

The PFAM database, PFAM version 2.1, (Sonnhammer, Nucl. Acids Res., 26:320-322, 1998)) consists of a series of multiple sequence alignments; one alignment for each protein family. Each multiple sequence alignment is converted into a probability model called a Hidden Markov Model, or HMM, that represents the position-specific variation among the sequences that make up the multiple sequence alignment (see, e.g., Durbin, et al., Biological sequence analysis: probabilistic models of proteins and nucleic acids, Cambridge University Press, 1998 for the theory of HMMs). The program HMMER version 1.8 (Sean Eddy, Washington University in Saint Louis) was used to compare the predicted protein sequence for each Query sequence (SEQ ID NO:Y in Table 1B.1) to each of the HMMs derived from PFAM version 2.1. A HMM derived from PFAM version 2.1 was said to be a significant match to a polypeptide of the invention if the score returned by HMMER 1.8 was greater than 0.8 times the HMMER 1.8 score obtained with the most distantly related known member of that protein family. The description of the PFAM family which shares a significant match with a polypeptide of the invention is listed in column 5 of Table 2, and the database accession number of the PFAM hit is provided in column 6. Column 7 provides the score returned by HMMER version 1.8 for the alignment. Columns 8 and 9 delineate the polynucleotides of SEQ ID NO:X which encode the polypeptide sequence which show a significant match to a PFAM protein family.

As mentioned, columns 8 and 9 in Table 2, “NT From” and “NT To”, delineate the polynucleotides of “SEQ ID NO:X” that encode a polypeptide having a significant match to the PFAM/NR database as disclosed in the fifth column. In one embodiment, the invention provides a protein comprising, or alternatively consisting of, a polypeptide encoded by the polynucleotides of SEQ ID NO:X delineated in columns 8 and 9 of Table 2. Also provided are polynucleotides encoding such proteins, and the complementary strand thereto.

The nucleotide sequence SEQ ID NO:X and the translated SEQ ID NO:Y are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, the nucleotide sequences of SEQ ID NO:X are useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA contained in ATCC Deposit No:Z. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling immediate applications in chromosome mapping, linkage analysis, tissue identification and/or typing, and a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ ID NO:Y may be used to generate antibodies which bind specifically to these polypeptides, or fragments thereof, and/or to the polypeptides encoded by the cDNA clones identified in, for example, Table 1A and/or 1B.

Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).

Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X, and a predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA containing cDNA ATCC Deposit No:Z (e.g., as set forth in columns 2 and 3 of Table 1A and/or as set forth, for example, in Table 1B, 6, and 7). The nucleotide sequence of each deposited clone can readily be determined by sequencing the deposited clone in accordance with known methods. Further, techniques known in the art can be used to verify the nucleotide sequences of SEQ ID NO:X. The predicted amino acid sequence can then be verified from such deposits. Moreover, the amino acid sequence of the protein encoded by a particular clone can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence. TABLE 2 PFam/NR Score/ cDNA SEQ Analysis Accession Percent NT NT Clone ID Contig ID: ID NO: X Method PFam/NR Description Number Identity From To H6EDM64 841331 11 WUblastx.64 (Q9UID3) ANG2. Q9UID3 90% 928 2451 36% 203 310 36% 931 1038 95% 191 871 HACBJ56 847112 13 WUblastx.64 (Q9D2Q2) 2310079F23RIK PROTEIN. Q9D2Q2 65% 98 286 HACBS22 847113 14 WUblastx.64 (O60266) ADENYLATE CYCLASE TYPE III (EC CYA3_HUMAN 89% 6 416 4.6.1.1) (ADENYLATE 25% 1547 2299 18% 917 1111 93% 416 2449 HADMB15 847116 18 WUblastx.64 (Q9BVH1) SIMILAR TO DLXIN-1. Q9BVH1 100% 8 109 HAGCC87 638587 20 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA. Q9BGW3 65% 992 1105 PROTEIN. 36% 54 116 57% 801 980 HAGFS57 847120 22 WUblastx.64 (Q9Y485) X-LIKE 1 PROTEIN. Q9Y485 58% 9 872 HAGHN57 773286 23 WUblastx.64 (O60416) WUGSC: H_RG276O03.2 PROTEIN. O60416 98% 65 1444 HAJAA47 534670 25 WUblastx.64 (Q9NZA3) CDA14. Q9NZA3 100% 17 157 HAJAY92 845601 26 WUblastx.64 (O00549) ORF2-LIKE PROTEIN (FRAGMENT). O00549 53% 2226 2318 26% 769 915 38% 1653 1769 31% 1721 2242 HAJBV67 866415 27 WUblastx.64 (Q9HD45) TRANSMEMBRANE 9 T9S3_HUMAN 100% 13 126 SUPERFAMILY PROTEIN MEMBER 3 PRECU 93% 116 1681 HARAE26 560598 29 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS, CLONE Q9H743 65% 1204 1076 COL03536. 75% 1068 925 HBAGD86 838799 31 WUblastx.64 (Q14287) HYPOTHETICAL PROTEIN Q14287 37% 801 559 (FRAGMENT). HBGBC29 691473 32 WUblastx.64 (O60513) BETA-1,4- B4G4_HUMAN 61% 1 78 GALACTOSYLTRANSFERASE 4 (EC 2.4.1.—) 98% 65 1021 (BET HBHAA05 603174 33 WUblastx.64 (Q9H387) PRO2550. Q9H387 71% 676 386 HBHAA81 846465 34 WUblastx.64 (Q9D1G3) 1110011D13RIK PROTEIN. Q9D1G3 89% 1329 1502 79% 28 1329 HBJAB02 837309 35 WUblastx.64 (Q9NXT6) CDNA FLJ20062 FIS, CLONE Q9NXT6 70% 2 1210 COL01508. HBJAC40 841235 36 WUblastx.64 (Q9P112) CHROMOSOME 16 OPEN READING Q9P112 100% 8 73 FRAME 5. 36% 5 70 57% 11 52 53% 85 180 100% 192 632 HBJCR46 815649 37 HMMER PFAM: WD domain, G-beta repeat PF00400 36.6 790 867 2.1.1 WUblastx.64 (Q9DC22) 1200006M05RIK PROTEIN. Q9DC22 96% 207 611 73% 568 2763 HBJEL16 847030 39 WUblastx.64 (O95297) PROTEIN ZERO RELATED PROTEIN. O95297 98% 285 491 HBJKD16 853358 41 WUblastx.64 (Q9NXS4) CDNA FLJ20080 FIS, CLONE Q9NXS4 91% 8 1528 COL03184. HBMUH74 866160 42 WUblastx.64 (Q9NVW8) CDNA FLJ10462 FIS, CLONE Q9NVW8 100% 11 427 NT2RP1001494, WEAKLY SIMILAR TO MAL HBQAB79 810542 43 WUblastx.64 (Q9UQ32) AD 3 (FRAGMENT). Q9UQ32 82% 323 204 HBXCM66 639039 44 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, CLONE Q9H728 65% 988 809 COL04765. 77% 836 690 HBXCX15 637542 45 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 41% 726 827 PROTEIN. 52% 578 730 HCDBO32 831942 46 WUblastx.64 (AAH17472) Hypothetical 21.3 kDa protein. AAH17472 69% 643 801 100% 239 583 HCEDR26 771144 47 WUblastx.64 (Q9H919) CDNA FLJ13078 FIS, CLONE Q9H919 66% 1157 1095 NT2RP3002002. 66% 1345 1184 HCEFG93 745400 49 WUblastx.64 (Q9H387) PRO2550. Q9H387 66% 1178 1134 80% 1114 1052 76% 1323 1186 HCEFZ82 831745 50 WUblastx.64 (Q9BV23) SIMILAR TO LIPASE PROTEIN. Q9BV23 95% 594 782 100% 17 604 HCFLN88 610000 51 WUblastx.64 (Q9BQE9) SIMILAR TO B-CELL Q9BQE9 87% 278 475 CLL/LYMPHOMA 7B (UNKNOWN) (PROTEIN FOR MGC HCHAB84 834326 52 WUblastx.64 (Q9BRV3) STROMAL CELL PROTEIN. Q9BRV3 89% 82 744 HCNSD29 862314 56 WUblastx.64 (O75400) HUNTINGTIN-INTERACTING O75400 82% 628 1605 PROTEIN HYPA/FBP11 (FRAGMENT). 78% 337 489 HDPDI72 897277 62 WUblastx.64 adult-specific brush border protein - rabbit pir|C45665|C45665 64% 180 230 83% 11 100 HDPGE24 801947 63 WUblastx.64 (Q9P195) PRO1722. Q9P195 65% 1413 1291 43% 1388 1278 77% 2528 2394 47% 2182 2078 75% 1774 1751 62% 2604 2557 68% 1301 1167 HDPIE44 899328 64 WUblastx.64 (Q9D666) 4632417G13RIK PROTEIN. Q9D666 62% 102 2453 HDPIU94 813352 65 WUblastx.64 (Q9BVF7) SIMILAR TO HYPOTHETICAL Q9BVF7 99% 63 1703 PROTEIN FLJ10422. HDPIY31 886159 66 WUblastx.64 hypothetical protein DKFZp434N1429.1 - human pir|T46448|T46448 72% 1714 1899 (fragment) HDPOC24 777493 67 WUblastx.64 (Q9H8K1) CDNA FLJ13518 FLS, CLONE Q9H8K1 100% 62 208 PLACE1005799. HDPPQ30 684292 69 WUblastx.64 (Q9H387) PRO2550. Q9H387 51% 807 727 79% 1042 815 HDQHM36 852328 70 WUblastx.64 (Q9N083) UNNAMED PORTEIN PRODUCT. Q9N083 69% 1129 1257 50% 965 1153 HE6CS65 762960 73 WUblastx.64 (Q9H7C6) CDNA: FLJ21047 FIS, CLONE Q9H7C6 98% 938 1378 CAS00253. HE6FU11 827236 74 HEMMER PFAM: von Willebrand factor type A domain PF00092 184.7 244 771 2.1.1 WUblastx.64 (O95460) MATRILIN-4 PRECURSOR. MTN4_HUMAN 77% 145 789 45% 782 907 41% 791 925 50% 794 907 38% 863 1498 33% 190 741 98% 782 1642 HE8BQ49 589443 76 WUblastx.64 hypothetical protein - human transposon MER37 pir|S72482|S72482 75% 343 474 64% 105 248 HE8SG96 862016 77 WUblastx.64 (Q9P195) PRO1722. Q9P195 58% 1997 1845 63% 1854 1687 HE9EA10 827796 78 WUblastx.64 laminin alpha-1 chain precursor - human pir|S14458|S14458 99% 761 1891 27% 878 1840 25% 1142 1876 HEAAW94 847340 80 WUblastx.64 (Q9UEV9) ACTIN-BINDING PROTEIN Q9UEV9 94% 285 890 HOMOLOG ABP-278. 41% 285 884 38% 285 884 36% 285 872 35% 285 884 34% 285 884 34% 285 878 32% 303 887 33% 285 881 33% 285 878 31% 285 869 29% 288 887 30% 279 884 31% 285 863 36% 414 848 30% 288 884 32% 429 857 31% 309 824 26% 321 824 38% 285 539 37% 552 824 HEBFR46 847064 84 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, CLONE Q9NX85 80% 1111 1022 KAIA0536. 84% 1265 1110 HEBGE07 798096 85 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, CLONE Q9NX85 79% 1851 1720 KAIA0536. HFEAY59 658685 89 WUblastx.64 (Q9Z320) C29. Q9Z320 67% 50 1153 HFEBO17 852218 90 WUblastx.64 (BAB55130) CDNA FLJ14559 fis, clone BAB55130 100% 523 624 NT2RM2001998. 91% 606 809 HFIJA68 847074 91 WUblastx.64 (Q9UHE8) SIX TRANSMEMBRANE STEA_HUMAN 89% 13 399 EPITHELIAL ANTIGEN OF PROSTATE. HFKES05 827572 92 WUblastx.64 (BAB55088) CDNA FLJ14496 fis, clone BAB55088 85% 84 314 NT2RM1000035. 94% 367 1722 HFVHW43 570948 96 WUblastx.64 (Q9BGX4) HYPOTHETICAL 13.8 KDA Q9BGX4 69% 1209 1093 PROTEIN. HGBER72 826710 97 WUblastx.64 (Q9H387) PRO2550. Q9H387 71% 1061 969 78% 1104 1063 77% 1237 1103 HGBHP91 693011 98 WUblastx.64 hypothetical protein (L1H 3′ region) - human pir|B34087|B34087 52% 541 491 44% 537 34 HHEAK45 765278 100 WUblastx.64 (Q9NPB0) DJ202I21.1 (NOVEL PROTEIN) Q9NPB0 68% 1949 1458 (CDNA FLJ11101 FIS, CLONE PLACE10 HHEOW19 886174 101 WUblastx.64 (O18973) RAB5 GDP/GTP EXCHANGE O18973 77% 417 623 FACTOR, RABEX5. 91% 611 715 56% 166 378 92% 129 167 HHFEB79 1300768 102 WUblastx.64 (Q92545) RW1 PROTEIN (FRAGMENT). RW1_HUMAN 74% 708 2387 80% 6 590 32% 1984 2148 HHFEB79 863749 256 WUblastx.64 Similar to a C. elegans protein encoded in cosmid dbj|BAA13387.1| 69% 1303 2400 C27F2 (U40419) [Homo sapiens] 80% 601 1185 HHFFS40 824059 104 WUblastx.64 (Q9H4A6) GOLGI PROTEIN. Q9H4A6 100% 3 251 HHPFP26 753269 106 WUblastx.64 (Q9BQG8) HYPOTHETICAL 32.5 KDA Q9BQG8 100% 906 1742 PROTEIN. HHSBI65 801910 109 WUblastx.64 (Q9H5W9) CDNA: FLJ22888 FIS, CLONE Q9H5W9 100% 270 407 KAT03934. 94% 479 1300 HISAT67 843549 110 WUblastx.64 (Q9UH94) PROLACTIN REGULATORY Q9UH94 88% 219 797 ELEMENT-BINDING PROTEIN (PROLACTIN 91% 788 1447 REGU HISBA38 561711 111 WUblastx.64 (Q9H387) PRO2550. Q9H387 53% 919 836 53% 996 907 51% 842 687 HJBCU75 638329 112 WUblastx.64 (O45030) STRABISMUS. O45030 44% 199 426 52% 464 964 HJMAA03 824062 113 WUblastx.64 (Q9N032) UNNAMED PROTEIN PRODUCT. Q9N032 71% 415 528 HJPCH08 840365 114 WUblastx.64 (O95235) RABKINESIN-6 (RAB6- RB6K_HUMAN 93% 9 596 INTERACTING KINESIN-LIKE PROTEI HKABU43 838573 115 WUblastx.64 (AAH03633) Translocase of outer mitochondrial AAH03633 100% 33 62 membr 92% 26 1597 HLDQU79 740755 119 WUblastx.64 (O75477) KE04P. O75477 100% 105 1142 HLDQU79 837599 257 blastx.2 KE04P. sp|O75477|O75477 99% 81 1118 HLHAP05 638476 120 WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS, CLONE Q9HA67 55% 1553 1500 MAMMA1000472. 72% 1650 1585 77% 1807 1646 HLHBS54 837503 121 WUblastx.64 (Q9NZV5) SELENOPROTEIN N PRECURSOR. SELN_HUMAN 92% 1 1455 HLICE88 840321 123 WUblastx.64 fibrinogen gamma-A chain precursor [validated] - pir|A90470|FGHUG 89% 3 584 human HLQAS12 886180 124 WUblastx.64 (Q9XTA8) LECTIN-LIKE OXIDIZED LDL Q9XTA8 71% 690 842 RECEPTOR. 52% 364 711 HLYGY91 658703 128 WUblastx.64 (Q9H8N0) CDNA FLJ13386 FIS, CLONE Q9H8N0 94% 221 391 PLACE1001104, WEAKLY SIMILAR TO MYO HMDAB29 584789 129 WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, CLONE Q9NX17 72% 1186 890 KAT08285. HMEDE24 837027 131 WUblastx.64 (Q9BVH9) SIMILAR TO GLUCOSE Q9BVH9 94% 188 1159 REGULATED PROTEIN, 58 KDA. 42% 101 742 HMEDI90 840077 132 WUblastx.64 (Q9HBA3) RAB3 INTERACTING PROTEIN Q9HBA3 100% 81 794 VARIANT 4 (FRAGMENT). HMQAI38 589964 136 WUblastx.64 immune-responsive gene 1 - mouse (fragment) pir|I54546|I54546 71% 11 1363 HMUAN45 833072 138 WUblastx.64 (BAB55441) CDNA FLJ14993 fis, clone BAB55441 70% 684 1238 Y79AA1001874, w 65% 239 955 100% 1247 1516 HMVBC31 825598 139 WUblastx.64 (O60725) PROTEIN-S ISOPRENYLCYSTEINE ICMT_HUMAN 80% 747 938 O-METHYLTRANSFERASE (E 87% 121 789 HMWBL03 822861 140 WUblastx.64 (Q9BWT1) C-MYC TARGET JP1. Q9BWT1 85% 137 1240 HMWCG28 847413 141 WUblastx.64 (Q9P1S9) KINASE DEFICIENT PROTEIN KDP Q9P1S9 84% 35 892 (FRAGMENT). HNFCY57 877653 143 WUblastx.64 (AAL12497) Cryopyrin. AAL12497 91% 8 2203 HNGAK51 603910 145 WUblastx.64 (O60448) NEURONAL THREAD PROTEIN O60448 61% 563 601 AD7C-NTP. 67% 733 915 65% 702 878 74% 714 914 HNGJB41 852178 151 WUblastx.64 probable oxysterol-binding protein DJ430N08.1 - pir|T02435|T02435 100% 128 9 human (fragment) HNHCT47 634691 156 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, CLONE Q9H728 46% 434 396 COL04765. 56% 621 448 HNHKI74 777856 157 WUblastx.64 (Q9BGX7) HYPOTHETICAL 13.0 KDA Q9BGX7 64% 350 541 PROTEIN. HOACG07 792928 159 WUblastx.64 (Q9GZN8) DJ1009E24.3 (A NOVEL PROTEIN) Q9GZN8 99% 183 704 (CDNA FLJ14158 FIS, CLONE NT2R HOEBK60 789396 161 WUblastx.64 (Q9H916) CDNA FLJ13081 FIS, CLONE Q9H916 98% 132 1916 NT2RP3002033. 100% 14 109 88% 106 159 HOFMO16 596835 162 HMMER PFAM: 3-beta hydroxysteroid PF01073 68.3 149 346 2.1.1 dehydrogenase/isomerase family WUblastx.64 (Q9BSN9) 3 BETA-HYDROXY-DELTA 5-C27- Q9BSN9 75% 11 184 STEROID OXIDOREDUCTASE. 83% 349 438 94% 290 346 HOFNB74 762821 163 WUblastx.64 (Q99JH1) HYPOTHETICAL 17.7 KDA PROTEIN. Q99JH1 72% 44 187 97% 199 471 HOHBO66 853375 164 WUblastx.64 (Q9NY61) DED PROTEIN (APOPTOSIS Q9NY61 94% 1322 828 ANTAGONIZING TRANSCRIPTION FACTOR). 88% 844 212 HORBV76 839270 166 WUblastx.64 (Q9Y2B2) PHOSPHATIDYLINOSITOL Q9Y2B2 91% 30 761 GLYCAN, CLASS L (EC 3.5.—.—) (PIG-L PRO HOSDO75 862049 167 WUblastx.64 (Q9D099) 1110057L18RIK PROTEIN. Q9D099 89% 11 202 88% 259 630 HOUDE92 580866 169 WUblastx.64 (Q9HBT2) HYPOTHETICAL 17.2 KDA Q9HBT2 96% 21 245 PROTEIN. HPCAL26 762822 170 WUblastx.64 (O95084) SERINE PROTEASE O95084 98% 398 640 (HYPOTHETICAL 43.0 KDA PROTEIN) 76% 135 497 (PROTEASE, S HPFCI36 855966 173 WUblastx.64 (Q9NX47) CDNA FLJ20445 FIS, CLONE Q9NX47 100% 9 320 KAT05170. HPMCV30 612870 177 WUblastx.64 (Q9BVD9) UNKNOWN (PROTEIN FOR Q9BVD9 76% 384 334 MGC: 5149). 68% 590 399 HPRBH85 695752 178 WUblastx.64 (BAB55300) CDNA FLJ14784 fis, clone BAB55300 62% 2 616 NT2RP4000713. 86% 534 1085 HPRCD35 853551 179 WUblastx.64 hypothetical protein DKFZp762L1710.1 - human pir|T50629|T50629 100% 320 613 (fragment) 57% 2 499 HPRCM72 813512 180 WUblastx.64 (Q9D3K9) 2810468K05RIK PROTEIN. Q9D3K9 45% 296 526 HPTRE80 884167 181 WUblastx.64 (O43819) SCO2 PROTEIN HOMOLOG SCO2_HUMAN 85% 779 39 PRECURSOR. HPTRI42 655362 182 WUblastx.64 (Q9BVA7) UNKNOWN (PROTEIN FOR Q9BVA7 85% 3 611 MGC: 5621). HPTRM02 812879 183 WUblastx.64 (Q9UJU6) SRC HOMOLOGY 3 DOMAIN- Q9UJU6 92% 332 940 CONTAINING PROTEIN HIP-55 (DREBRIN F). 97% 2 106 96% 98 190 HPTVI96 636064 185 WUblastx.64 (Q9H5X3) HYPOTHETICAL 13.8 KDA Q9H5X3 77% 42 416 PROTEIN. HRDAI17 560720 187 WUblastx.64 (Q9NUM6) CDNA FLJ11267 FIS, CLONE Q9NUM6 59% 1305 1475 PLACE1009174. HRDDQ39 840405 188 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, CLONE Q9NX85 53% 582 436 KAIA0536. 65% 775 578 HRDEX93 816046 189 WUblastx.64 (Q9UBV8) PEFLIN. Q9UBV8 100% 313 864 HRTAP63 780698 190 WUblastx.64 (Q9Y3C9) CGI-127 PROTEIN. Q9Y3C9 100% 498 860 HSAWZ40 634000 193 WUblastx.64 (O00549) ORF2-LIKE PROTEIN (FRAGMENT). O00549 64% 951 610 60% 613 8 HSHAX04 812178 196 WUblastx.64 peptidylprolyl isomerase (EC 5.2.1.8) A - human pir|S66681|S66681 96% 14 916 HSNBM34 635131 198 WUblastx.64 acyl-CoA dehydrogenase (EC 1.3.99.—) very-long- pir|S54183|S54183 84% 1548 1979 chain specific - human 100% 251 1546 HSRFD18 840771 199 WUblastx.64 (Q9H941) CDNA FLJ13033 FIS, CLONE Q9H941 100% 437 559 NT2RP3001126. HSSEF77 658725 200 WUblastx.64 (O95637) WW DOMAIN BINDING PROTEIN-1. O95637 42% 10 246 83% 296 829 HSYBI06 740766 203 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 69% 916 954 PROTEIN. 78% 821 913 HT5GR59 801930 205 WUblastx.64 (O60496) DOCKING PROTEIN. O60496 72% 70 1284 HTDAA78 566861 206 WUblastx.64 (Q9D8E7) 5830443F10RIK PROTEIN. Q9D8E7 58% 84 302 HTEAG62 812332 207 WUblastx.64 (Q9Y5Z7) HOST CELL FACTOR 2. Q9Y5Z7 60% 1 57 93% 14 2011 30% 107 631 HTECB02 806305 208 WUblastx.64 (AAK39520) BTB domain protein (Fragment). AAK39520 95% 33 1211 HTEJD29 695798 211 WUblastx.64 (Q60713) REVERSE TRANSCRIPTASE. Q60713 42% 1115 1285 47% 874 1089 HTENR63 877952 213 WUblastx.64 (Q9HD71) HYPOTHETICAL NUCLEAR Q9HD71 33% 1278 1358 FACTOR SBBI22. 78% 26 1168 HTGBK95 834490 214 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 66% 126 55 PROTEIN. 70% 235 116 HTGGM44 842856 215 WUblastx.64 probable phosphodiesterase I (BC 3.1.4.1) - human pir|T43461|T43461 100% 1400 1924 (fragment) 83% 1925 2488 HTLBT80 840045 217 WUblastx.64 (Q9NQQ7) BA394O2.1 (CGI-15 PROTEIN). Q9NQQ7 76% 1214 1405 74% 804 1223 47% 780 845 78% 313 825 HTLCX82 847091 218 WUblastx.64 (Q9BTZ4) SIMILAR TO EXPRESSED Q9BTZ4 100% 127 258 SEQUENCE 2 EMBRYONIC LETHAL 72% 237 629 (FRAGMENT). HTLEV48 723799 220 WUblastx.64 (BAB55550) Bk125H2.1 protein. BAB55550 94% 10 825 HTLFA13 535937 221 WUblastx.64 (Q9UHT1) PRO1902 PROTEIN. Q9UHT1 57% 1118 873 HTLGI89 835069 222 WUblastx.64 (Q9BXS5) CLATHRIN-ASSOCIATED PROTEIN Q9BXS5 98% 104 682 AP47. 99% 675 1370 HTNBK13 831967 223 WUblastx.64 (Q9Y3M2) HYPOTHETICAL 14.5 KDA Q9Y3M2 81% 123 500 PROTEIN. HTOAM11 664508 224 WUblastx.64 (Q9H5R3) CDNA: FLJ23147 FIS, CLONE Q9H5R3 77% 428 363 LNG09295. 75% 586 425 HTPCO75 853645 227 WUblastx.64 (O00549) ORF2-LIKE PROTEIN (FRAGMENT). O00549 43% 325 26 36% 1318 1253 HTTCB60 853401 228 WUblastx.64 (Q9HAW0) RNA POLYMERASE III Q9HAW0 90% 6 881 TRANSCRIPTION INITIATION FACTOR BRFU. HTTDN24 766485 229 WUblastx.64 (Q9BVN5) HYPOTHETICAL 120.6 KDA Q9BVN5 95% 628 1725 PROTEIN. 32% 937 1593 95% 3 629 32% 1114 1596 HTTEE41 840950 230 WUblastx.64 (P78371) T-COMPLEX PROTEIN 1, BETA TCPB_HUMAN 98% 92 1696 SUBUNIT (TCP-1-BETA) (CC HTWEH94 561680 231 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 60% 1150 929 PROTEIN. HTXFA72 853410 234 WUblastx.64 (Q9N083) UNNAMED PORTEIN PRODUCT. Q9N083 59% 1688 1557 66% 1839 1681 HTXJD85 840391 235 WUblastx.64 (Q9HAD8) CDNA FLJ11786 FIS, CLONE Q9HAD8 52% 1093 818 HEMBA1006036. HUFCL31 801938 238 WUblastx.64 (Q9D311) 9030623N16RIK PROTEIN. Q9D311 60% 280 1224 HUSCJ14 894699 240 WUblastx.64 tex261 protein - mouse pir|S47481|S47481 99% 74 661 HUVDJ48 564853 241 WUblastx.64 SHORT ISOFORM OF Q9P2N4 sp_vs|Q9P2N4- 92% 1510 1668 01|Q9P2N4 HWBBU75 780360 242 WUblastx.64 (Q9R189) MUNC13-4 PROTEIN. Q9R189 82% 1454 2362 73% 913 1434 80% 194 952 62% 2229 2729 31% 1586 1711 34% 401 532 HWBCN36 722259 243 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 69% 1007 900 PROTEIN. 57% 887 846 HWBDJ08 762860 244 WUblastx.64 probable pol polyprotein-related protein 4 - rat pir|S21348|S21348 47% 901 833 43% 1262 1131 53% 1134 904 HWLGP26 834770 246 WUblastx.64 (Q9NP87) DNA POLYMERASE MU. Q9NP87 93% 674 760 100% 269 298 94% 295 465 87% 432 623 100% 3 254 HILCA24 869856 247 WUblastx.64 (Q9NUU6) CDNA FLJ11127 FIS, CLONE Q9NUU6 95% 104 1171 PLACE1006225. HILCA24 782450 260 WUblastx.64 (Q9NUU6) CDNA FLJ11127 FIS, CLONE Q9NUU6 73% 103 159 PLACE1006225. 100% 168 1169 HYABC84 865064 248 WUblastx.64 (Q9H429) DJ756N5.2 (A NOVEL PROTEIN Q9H429 92% 163 618 (DKFZP727M231) SIMILAR TO TRP4-AS HYABC84 789854 261 WUblastx.64 (Q99L03) SIMILAR TO TRP4-ASSOCIATED Q99L03 89% 209 553 PROTEIN TAP1 (FRAGMENT). HPWTF23 844775 249 HMMER PFAM: TSC-22/dip/bun family PF01166 146.4 442 621 2.1.1 WUblastx.64 (Q99576) GLUCOCORTICOID-INDUCED GILZ_HUMAN 94% 271 672 LEUCINE ZIPPER PROTEIN (DEL HPWTF23 843700 262 HMMER PFAM: TSC-22/dip/bun family PF01166 146.4 442 621 2.1.1 WUblastx.64 (Q99576) GLUCOCORTICOID-INDUCED GILZ_HUMAN 94% 271 672 LEUCINE ZIPPER PROTEIN (DEL HGCAC19 851527 251 WUblastx.64 (Q9UIE9) WUGSC: H_DJ0687K01.2 PROTEIN. Q9UIE9 34% 984 1124 31% 1546 1863 96% 361 1047 24% 993 1124 22% 984 1124 40% 1002 1124 27% 984 1124 27% 981 1124 25% 984 1088 31% 984 1124 23% 984 1124 29% 984 1124 29% 984 1124 32% 1023 1124 26% 586 801 95% 2017 2712 HGCAC19 842540 264 WUblastx.64 (Q9H6A1) CDNA: FLJ22454 FIS, CLONE Q9H6A1 34% 982 1122 HRC09703 (FRAGMENT). 100% 182 208 31% 982 1122 29% 982 1122 40% 1000 1122 27% 982 1122 29% 982 1122 27% 979 1122 21% 982 1119 24% 991 1122 23% 982 1122 96% 314 1045 HGCAC19 801999 265 WUblastx.64 (Q9H6A1) CDNA: FLJ22454 FIS, CLONE Q9H6A1 34% 984 1124 HRC09703 (FRAGMENT). 100% 184 210 31% 984 1124 29% 984 1124 40% 1002 1124 27% 984 1124 29% 984 1124 27% 981 1124 21% 984 1121 24% 993 1124 23% 984 1124 96% 316 1056 HEQBJ01 876546 252 WUblastx.64 (Q9LVQ7) ZINC FINGER PROTEIN. Q9LVQ7 34% 424 849 HEQBJ01 861786 266 WUblastx.64 (Q9LVQ7) ZINC FINGER PROTEIN. Q9LVQ7 34% 424 849 HE8FD92 901142 254 WUblastx.64 (Q9UJI9) HYPOTHETICAL 105.9 KDA Q9UJI9 76% 31 480 PROTEIN. 56% 31 411 67% 217 408 67% 217 408 63% 217 411 63% 217 411 60% 217 411 53% 217 411 59% 31 126 56% 31 126 56% 31 126 56% 31 126 39% 58 126 HE8FD92 869847 270 WUblastx.64 (Q9UJI9) HYPOTHETICAL 105.9 KDA Q9UJI9 74% 4 609 PROTEIN. 59% 4 540 50% 1 255 63% 346 540 63% 346 540 60% 346 540 49% 1 255 48% 1 255 53% 346 540 41% 4 255 33% 40 255 HE8FD92 856544 271 WUblastx.64 (Q9UJI9) HYPOTHETICAL 105.9 KDA Q9UJI9 84% 419 1414 PROTEIN. 71% 2 1060 76% 419 1345 61% 2 613 45% 203 1060 40% 449 1345 52% 2 328 33% 605 1345 46% 47 328 HBDAB91 864374 255 WUblastx.64 (O00370) PUTATIVE P150. O00370 40% 907 833 35% 849 307 HBDAB91 789532 273 WUblastx.64 (O00370) PUTATIVE P150. O00370 40% 587 513 34% 529 5 RACE Protocol for Recovery of Full-Length Genes

Partial cDNA clones can be made full-length by utilizing the rapid amplification of cDNA ends (RACE) procedure described in Frohman, M. A., et al., Proc. Natl. Acad. Sci. USA, 85:8998-9002 (1988). A cDNA clone missing either the 5′ or 3′ end can be reconstructed to include the absent base pairs extending to the translational start or stop codon, respectively. In some cases, cDNAs are missing the start codon of translation, therefor. The following briefly describes a modification of this original 5′ RACE procedure. Poly A+ or total RNA is reverse transcribed with Superscript II (Gibco/BRL) and an antisense or complementary primer specific to the cDNA sequence. The primer is removed from the reaction with a Microcon Concentrator (Amicon). The first-strand cDNA is then tailed with dATP and terminal deoxynucleotide transferase (Gibco/BRL). Thus, an anchor sequence is produced which is needed for PCR amplification. The second strand is synthesized from the dA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer Cetus), an oligo-dT primer containing three adjacent restriction sites (XhoI, SalI and ClaI) at the 5′ end and a primer containing just these restriction sites. This double-stranded cDNA is PCR amplified for 40 cycles with the same primers as well as a nested cDNA-specific antisense primer. The PCR products are size-separated on an ethidium bromide-agarose gel and the region of gel containing cDNA products the predicted size of missing protein-coding DNA is removed. cDNA is purified from the agarose with the Magic PCR Prep kit (Promega), restriction digested with XhoI or SalI, and ligated to a plasmid such as pBluescript SKII (Stratagene) at XhoI and EcoRV sites. This DNA is transformed into bacteria and the plasmid clones sequenced to identify the correct protein-coding inserts. Correct 5′ ends are confirmed by comparing this sequence with the putatively identified homologue and overlap with the partial cDNA clone. Similar methods known in the art and/or commercial kits are used to amplify and recover 3′ ends.

Several quality-controlled kits are commercially available for purchase. Similar reagents and methods to those above are supplied in kit form from Gibco/BRL for both 5′ and 3′ RACE for recovery of full length genes. A second kit is available from Clontech which is a modification of a related technique, SLIC (single-stranded ligation to single-stranded cDNA), developed by Dumas et al., Nucleic Acids Res., 19:5227-32 (1991). The major differences in procedure are that the RNA is alkaline hydrolyzed after reverse transcription and RNA ligase is used to join a restriction site-containing anchor primer to the first-strand cDNA. This obviates the necessity for the dA-tailing reaction which results in a polyT stretch that is difficult to sequence past.

An alternative to generating 5′ or 3′ cDNA from RNA is to use cDNA library double-stranded DNA. An asymmetric PCR-amplified antisense cDNA strand is synthesized with an antisense cDNA-specific primer and a plasmid-anchored primer. These primers are removed and a symmetric PCR reaction is performed with a nested cDNA-specific antisense primer and the plasmid-anchored primer.

RNA Ligase Protocol for Generating the 5′ or 3′ End Sequences to Obtain Full Length Genes

Once a gene of interest is identified, several methods are available for the identification of the 5′ or 3′ portions of the gene which may not be present in the original cDNA plasmid. These methods include, but are not limited to, filter probing, clone enrichment using specific probes and protocols similar and identical to 5′ and 3′ RACE. While the full length gene may be present in the library and can be identified by probing, a useful method for generating the 5′ or 3′ end is to use the existing sequence information from the original cDNA to generate the missing information. A method similar to 5′ RACE is available for generating the missing 5′ end of a desired full-length gene. (This method was published by Fromont-Racine et al., Nucleic Acids Res., 21(7):1683-1684 (1993)). Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of a population of RNA presumably containing full-length gene RNA transcript and a primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest, is used to PCR amplify the 5′ portion of the desired full length gene which may then be sequenced and used to generate the full length gene. This method starts with total RNA isolated from the desired source, poly A RNA may be used but is not a prerequisite for this procedure. The RNA preparation may then be treated with phosphatase if necessary to eliminate 5′ phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase if used is then inactivated and the RNA is treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5′ ends of messenger RNAs. This reaction leaves a 5′ phosphate group at the 5′ end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase. This modified RNA preparation can then be used as a template for first strand cDNA synthesis using a gene specific oligonucleotide. The first strand synthesis reaction can then be used as a template for PCR amplification of the desired 5′ end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known sequence of the gene of interest. The resultant product is then sequenced and analyzed to confirm that the 5′ end sequence belongs to the relevant gene.

The present invention also relates to vectors or plasmids which include such DNA sequences, as well as the use of the DNA sequences. The material deposited with the ATCC (e.g., as described in columns 2 and 3 of Table 1A, and/or as set forth in Table 1B, Table 6, or Table 7) is a mixture of cDNA clones derived from a variety of human tissue and cloned in either a plasmid vector or a phage vector, as described, for example, in Table 1A and Table 7. These deposits are referred to as “the deposits” herein. The tissues from which some of the clones were derived are listed in Table 7, and the vector in which the corresponding cDNA is contained is also indicated in Table 7. The deposited material includes cDNA clones corresponding to SEQ ID NO:X described, for example, in Table 1A and/or Table 1B (ATCC Deposit No:Z). A clone which is isolatable from the ATCC Deposits by use of a sequence listed as SEQ ID NO:X, may include the entire coding region of a human gene or in other cases such clone may include a substantial portion of the coding region of a human gene. Furthermore, although the sequence listing may in some instances list only a portion of the DNA sequence in a clone included in the ATCC Deposits, it is well within the ability of one skilled in the art to sequence the DNA included in a clone contained in the ATCC Deposits by use of a sequence (or portion thereof) described in, for example Tables 1A and/or Table 1B or Table 2, by procedures hereinafter further described, and others apparent to those skilled in the art.

Also provided in Table 1A and Table 7 is the name of the vector which contains the cDNA clone. Each vector is routinely used in the art. The following additional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector. Both phagemids may be transformed into E. coli strain XL-1 Blue, also available from Stratagene.

Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59-(1993). Vector lafmid BA (Bento Soares, Columbia University, New York, N.Y.) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR®2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ ID NO:X, SEQ ID NO:Y, and/or the deposited clone (ATCC Deposit No:Z). The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.

Also provided in the present invention are allelic variants, orthologs, and/or species homologs. Procedures known in the art can be used to obtain full-length genes, allelic variants, splice variants, full-length coding portions, orthologs, and/or species homologs of genes corresponding to SEQ ID NO:X or the complement thereof, polypeptides encoded by genes corresponding to SEQ ID NO:X or the complement thereof, and/or the cDNA contained in ATCC Deposit No:Z, using information from the sequences disclosed herein or the clones deposited with the ATCC. For example, allelic variants and/or species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for allelic variants and/or the desired homologue.

The polypeptides of the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.

The polypeptides may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below). It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification, such as multiple histidine residues, or an additional sequence for stability during recombinant production.

The polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified. A recombinantly produced version of a polypeptide, including the secreted polypeptide, can be substantially purified using techniques described herein or otherwise known in the art, such as, for example, by the one-step method described in Smith and Johnson, Gene 67:31-40 (1988). Polypeptides of the invention also can be purified from natural, synthetic or recombinant sources using techniques described herein or otherwise known in the art, such as, for example, antibodies of the invention raised against the polypeptides of the present invention in methods which are well known in the art.

The present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ID NO:X, and/or the cDNA sequence contained in ATCC Deposit No:Z. The present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X or a complement thereof, a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/or the polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1C. Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X, a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/or a polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1C are also encompassed by the invention. The present invention further encompasses a polynucleotide comprising, or alternatively consisting of, the complement of the nucleic acid sequence of SEQ ID NO:X, a nucleic acid sequence encoding a polypeptide encoded by the complement of the nucleic acid sequence of SEQ ID NO:X, and/or the cDNA contained in ATCC Deposit No:Z.

Moreover, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in Table 1C column 6, or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in Table 1C column 6, or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1C, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1C, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1C, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1C, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

Further, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1C which correspond to the same Clone ID (see Table 1C, column 1), or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in column 6 of Table 1C which correspond to the same Clone ID (see Table 1C, column 1), or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1C which correspond to the same Clone ID (see Table 1C, column 1) and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1C, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1C which correspond to the same Clone ID (see Table 1C, column 1) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1C which correspond to the same Clone ID (see Table 1C, column 1) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

Further, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1C which correspond to the same contig sequence identifier SEQ ID NO:X (see Table 1C, column 2), or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in column 6 of Table 1C which correspond to the same contig sequence identifier SEQ ID NO:X (see Table 1C, column 2), or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1C which correspond to the same contig sequence identifier SEQ ID NO:X (see Table 1C, column 2) and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1C, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1C which correspond to the same contig sequence identifier SEQ ID NO:X (see Table 1C, column 2) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1C which correspond to the same contig sequence identifier SEQ ID NO:X (see Table 1C, column 2) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (See Table 1C, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

Moreover, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of Table 1C column 6, or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in the same row of Table 1C column 6, or any combination thereof. In preferred embodiments, the polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in the same row of Table 1C column 6, wherein sequentially delineated sequences in the table (i.e. corresponding to those exons located closest to each other) are directly contiguous in a 5′ to 3′ orientation. In further embodiments, above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1C, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1C, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1C, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1C, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1C, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1C, column 2) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1C which correspond to the same Clone ID (see Table 1C, column 1), and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A, Table 1B, or Table 1C) or fragments or variants thereof. In preferred embodiments, the delineated sequence(s) and polynucleotide sequence of SEQ ID NO:X correspond to the same Clone ID. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of column 6 of Table 1C, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A, Table 1B, or Table 1C) or fragments or variants thereof. In preferred embodiments, the delineated sequence(s) and polynucleotide sequence of SEQ ID NO:X correspond to the same row of column 6 of Table 1C. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C and the 5′ 10 polynucleotides of the sequence of SEQ ID NO:X are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C and the 5′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X are directly contiguous Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of the sequence of SEQ ID NO:X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1C are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1C are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides, are also encompassed by the invention.

In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C and the 5′ 10 polynucleotides of another sequence in column 6 are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C and the 5′ 10 polynucleotides of another sequence in column 6 corresponding to the same Clone ID (see Table 1C, column 1) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one sequence in column 6 corresponding to the same contig sequence identifer SEQ ID NO:X (see Table 1C, column 2) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C and the 5′ 10 polynucleotides of another sequence in column 6 corresponding to the same row are directly contiguous. In preferred embodiments, the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C is directly contiguous with the 5′ 10 polynucleotides of the next sequential exon delineated in Table 1C, column 6. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

Table 3

Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. Accordingly, for each contig sequence (SEQ ID NO:X) listed in the fifth column of Table 1A and/or the fourth column of Table 1B, preferably excluded are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO:X, b is an integer of 15 to the final nucleotide of SEQ ID NO:X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a +14. More specifically, preferably excluded are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a and b are integers as defined in columns 4 and 5, respectively, of Table 3. In specific embodiments, the polynucleotides of the invention do not consist of at least one, two, three, four, five, ten, or more of the specific polynucleotide sequences referenced by the Genbank Accession No. as disclosed in column 6 of Table 3 (including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone). In no way is this listing meant to encompass all of the sequences which may be excluded by the general formula, it is just a representative example. All references available through these accessions are hereby incorporated by reference in their entirety. TABLE 3 cDNA SEQ ID Contig EST Disclaimer Clone ID NO: X ID: Range of a Range of b Accession #'s H6EDM64 11 841331 1-2596 15-2610 AL529288, AL514648, AL523579, AL523918, AL530571, AL528848, AL523917, AL523578, BE795355, BE614208, AL529287, BE797988, BE747962, BE798201, AL530750, BF689293, BE884814, BF508994, BE798313, BE613450, BE787266, AW131835, AL530749, BG248495, BE386285, BF526775, BE873469, BE299650, AL042569, BE621187, BG168950, AW410458, BE883794, BE869375, BF348689, AW239351, BE737181, BE734276, BF309636, BF129214, BG180549, AW410610, AW601905, BE621858, AA689552, BF310547, AW960649, BF953086, AL045821, BE882424, BF724804, BE019151, AW246108, BG179779, AW374338, AW675186, BE279317, BG011956, AI475847, AI394166, AI142042, AW068652, AI539419, AI970048, AI792316, AA536006, AW272491, BG012645, AI827847, BG254459, AI673493, AW007399, AI719374, AA994188, BG176564, AI707847, AW104963, AI220974, AA022523, BF807054, BG012634, BF803094, N24911, AW665019, AI458806, AA689495, AA480131, AI808412, N41812, W17347, BE772562, BG012642, BF807055, BE772573, BG011957, BG012641, AL514647, F22287, AI160580, AI149344, BE772556, AI870582, BE772568, AW801577, BG176616, AW801325, AW068651, AI197831, BE265961, AA483525, BE772566, BE772574, BE693737, AA687509, BE839398, BF799200, AA687451, AI201450, BF896481, BE772569, BE244158, BE772576, BE826728, AI452812, BE772561, AA317941, AA308425, AA745895, AW751437, BG256219, AA782657, BF373198, AA364848, AL039960, AA405870, AW963550, BE300303, N78953, AA112404, BE826586, AI061434, AI143698, AW087863, AI382254, AW731818, BE788591, AW304748, AI589259, AA357514, BF663656, AW673017, AW664622, AA524482, AW246627, BE831243, BE831271, BG055766, AI749023, AA380438, BF746714, BE839346, AW084279, AA113160, BF529848, AI160508, BF764174, BF752908, AA053148, AW842671, F32117, AI190107, BF752929, BE547478, AA977756, AA360528, AA022454, BF808843, BF813892, AI917965, BG011699, BG012316, BF373193, BG122581, AA622680, BF688484, BE772558, AA053706, AA733114, BG012318, AW880294, AA482098, BE256450, BE831281, BF765811, BF803085, BE243388, AA774840, AA576098, BE831236, BE772816, AF024631.2, BC007198.1, BC009285.1, AF096303.1, U73627.1, AF061779.1, AC004923.2, AF238378.3, AC000385.1. H6EEU40 12 757048 1-937 15-951 AL534759, AL521087, AL523775, AL518427, AL518354, AL517326, BE741563, BF569745, BF337372, BF570471, BF969174, BG032740, AL536265, BF026597, BE274743, BE546314, AL522079, BE538554, AW960892, BE395781, BE465235, BG167967, BE275462, AI160737, BF804270, BE538514, AA653290, BG163271, AI341701, W94467, AW084148, AI634272, AI634641, AI266283, AI366893, AW409760, AW075307, BF223869, AA604286, AI262840, AA479733, AI985719, W94359, AI271832, AW439127, AI740653, AI500535, AI674680, AW245294, BF032823, BE350203, AI869835, R85540, BF437722, AI394604, AA825592, AW469385, R60570, AI620873, AW470050, AA788601, BE300983, R72347, N77923, AA939017, R72299, R87968, R85120, Z41206, T16501, AA482633, H40664, AA297447, AA081389, R85549, AA558602, AW175922, AA987713, AI628307, AI199953, BG056252, AI382799, AA968853, AA148651, AI289139, AI281228, AA298765, F09249, W94940, AI282067, AI262509, AI200241, AV735503, AI921784, AI628244, T32046, AA302912, AI417848, AI468747, AW055372, AA857797, AA244103, AI581120, AA679586, AI634273, AA694158, AA946762, AA608791, AI124016, H46898, W46963, AA584396, AI797302, AL518355, AL523776, H27881, AL518428, H84434, N99004, AI540357, D31570, BF765616, AA132303, AA814926, BE812370, AW404688, AL532367, AL534760, AA887999, AL530884, AL526404, BE937700, R46056, AL517327, AL536266, R40219, AW468110, H24286, AA522908, AI567331, H26975, T81176, AW369400, T80775, AI952287, AW797699, BE782422, AA872110, BE613072, AW269694, BE870596, AA490287, AI336931, BE937686, BE741460, BE937697, AI910098, AI583322, BE962616, BE932414, AL533205, AI905196, AL521088, AA479862, AK000120.1, AL096714.1, BC007519.1. HACBJ56 13 847112 1-874 15-888 AA157001, BE348653, AW027639, AA534339, AW001883, AA363258, AW959379, T71037, AW953765, BE048583, BF878388, T67200, AW393348, AW393350, AW384705, AW386713, AA156760, AW055343, BF892732, BE140594. HACBS22 14 847113 1-3225 15-3239 AU124073, BG253611, AW965191, BG115564, BF032820, AW965203, BF306517, BF304908, BF306593, BF982389, BF033269, AW890326, BF983369, AI302793, BF591498, AI567467, AV711792, AA429582, AI422294, AI859789, AA433987, AA814217, AA252998, AA279301, AA411385, AI342153, BE328862, BF127455, BF223404, BE073310, AW131093, AI061457, AW886431, BF316718, AI418930, AI126382, BF334564, BF115589, BF229901, AI199632, AI083697, AI076499, AI565545, AI083759, AW168955, AI075711, AA451848, AI832008, AA278862, AA406270, AA039587, AA603155, AI654833, AI217940, T67815, AA004762, BG056988, AW166397, W48835, AA857111, AA099992, AI283878, AA156539, AI268898, AA311784, AA625982, AW081237, AI431333, AW337580, AA157697, AI142910, AA434158, AW953535, AA281247, AI886152, AA099991, AI222819, AA279346, AA464193, AW902181, H41843, AA292181, T41156, T41125, AA918848, AV725329, AW237010, R20286, AA864669, H53657, BG008052, R22827, AA366602, AA456430, AA323466, AA897397, AA399222, BG002413, AA278539, R15382, BF899835, BE746477, R73996, AW663090, F03040, BG005938, R23319, BG002290, F06777, AA431990, AA884057, AI696614, BG002306, AA743065, AW805802, T40225, AA004763, H41803, T26456, R49943, H78738, AA598528, H78725, BE242201, AW769702, H79499, AW804514, H79512, AW589498, R08207, AA446922, BG008055, R42123, AI040559, H53618, BE938610, R23242, BF943906, T41091, W49816, BG007599, BF746451, T40268, BF943900, BE242322, T26457, BG007600, AA779288, AA620918, AA345630, T67965, BF943907, BF230057, T40261, AL120752, R43626, AA159388, H69584, AA252997, BE247168, R73903, R46015, AW189448, BE241991, AI868154, AI953925, AI421607, BF869086, BE939781, AA894421, AA039586, AA324932, AI498022, AW965271, AW300921, AW965468, BF871875, W68610, BE242008, BF829222, AA333777, R08258, AA400456, BE769384, AA332944, BE267667, AI147721, R49942, BG121728, W42651, BF243188, BG170063, AA815037, BE257390, BE790941, BF808078, AW977805, AW291305, T81704, AB011083.1, AF033861.1, AK027857.1, AK027859.1, AF087963.1, BC002870.1. HACBT91 15 789939 1-827 15-841 AW957974, AW003857, AI820045, AI523911, AW084836, AI983096, AI333432, AW188197, BF338099, N41047, AI433769, AI379333, AW438811, AA927750, BE139611, AI435307, BF436802, AW613586, R71675, AA678318, AA748856, AA301830, AI337423, AW243869, AA577365, AI382805, AI926335, AA568182, R47922, AA057770, R50081, BE247721, AI539624, AI698267, AI224055, BE244865, AI365443, N47137, AA903242, AV707146, AW955723, AV702790, AV701751, AW962407, AV705416, AI535639, AV705047, AW954994, AV703012, AW957544, BF380516, AV729076, AV707458, AV706060, AV704785, AV701728, AV709232, AW957628, AW954206, AV709235, AV707753, AV686390, AW955616, AW961393, AV725497, AV729376, AV728436, AV697196, AW958846, AW963660, AW951562, AW949999, AI535660, AV728733, AV692600, AV727314, AV703766, AV705319, AW959907, AW950888, AV656903, AW956199, AW957853, AV704180, AV696106, AV706223, AW963378, AW964540, AV727238, AV705869, AV705811, AW953969, AV689111, AW961593, AV695545, AV702266, AW952064, AV704955, AW963868, AV705135, AI525856, AW949731, AW958280, AV686420, AV686100, AV726103, AV695752, AV693523, AV709551, AV702861, AW951707, AV694674, AV709101, AV698429, AV702372, AV697498, AW950597, AW952223, AV692691, AV706229, AW958916, AV701067, AV658334, AV728670, AV705562, AW949729, AW955152, AV684962, AV729378, AW949523, AW957102, AV705134, AV685966, AW955662, AI536138, AW956637, AV653325, AV705693, AV702498, AW950199, AV708203, AW964369, AV701643, AW950172, AV707002, AV725153, AV706136, AI557602, AW955904, AV727916, AW950411, AV707024, AW949529, AV706147, AW963601, AW953788, AV647006, AV702035, AV705520, AW954782, AW951743, AW957682, AV702172, AW966604, AV705453, AW952368, AW956762, AW962384, AV654287, AV708025, AV728309, AW950079, AV708980, AW965813, AW958901, AW959980, AW955841, AV705959, AV725697, AW950395, AV706910, AW959982, AW950443, AW950248, AV708850, AV707329, AV703635, AW954237, AV704798, AV703030, AV703542, AW959543, AW963011, AW963750, AW950671, AW955713, AV725948, AW949451, AW966756, AV729132, AV701881, AW949927, AV653809, AW955609, AV649672, AW950446, AW949351, AV702673, AW957110, AW954372, AV728874, AV685955, AW949530, AW959828, AW964111, AW960601, AV705185, AW966444, AW950012, AW962444, AV725001, AV703494, AW959806, AV705981, AW952403, AW957987, AW966603, AV726789, AV661704, AV706893, AW964673, AV727978, AV706459, AW953797, AV707414, AK025994.1, U94592.1, Y08991.1, Z30183.1, AF217994.1, U45328.1. HADDJ13 16 827273 1-2304 15-2318 AW575129, AW022897, AA010299, AU144131, AA669573, F11929, AL138228, AA634252, T66105, AA219059, R91924, R51726, AA856981, AA782322, AC079383.17, AC004552.1, Z95118.1, AF224669.1, AC018797.4, AC003035.1, AL161436.12, AC008625.5, AC002565.1, AC002350.1, AL390738.4, AC073593.13, AL354932.26, AC004491.1, AC011497.6, AC051619.7, AC008440.8, AF205588.1, AC007546.5, AC005250.1, AC016594.6, AC006038.2, AL031120.1, AC020658.6, Z84469.1, AC018719.4, AC006080.1, AF324890.1, AL354873.19, AL391259.15, AL162615.13, AL034372.33, AC018639.8, AL132777.4, AC004605.1, AL352978.6, AL160269.14, AL136000.4, AC024168.4, AL080275.20, AC090942.1, AC004685.1, AC008901.5, Z82198.2, AL121578.1, AC013734.4, AL133286.9, AC002091.1, AL356575.8, AC007934.7, AC005035.1, AL031311.1, AC005840.2, AL117337.25, AL035400.13, AC068724.7, AC007225.2, AL499604.9, AC005208.1, AL139785.5, AC002368.1, AC011484.4, AL162233.14, AC018637.3, AC091493.1, AL035555.10, AL136231.12, AP001714.1, AC044797.5, AC006211.1, AC009779.18, AL160155.19, AP000512.1, AC079754.4, AL391987.15, AP001732.1, AC083861.2, AC024060.5, AC025262.27, AL158069.16, AB023051.1, AC087311.22, AC078833.3, AC005670.1, AL391136.9, AL163267.2, AL080315.18, AC022201.4, AL138721.16, AC007318.4, AC005529.7, AL121594.6, AL136300.22, AL391114.12, AC006285.11, AL079342.17, AL031293.1, U82671.3, AC011310.3, U52111.2, AC018812.5, AL136365.9, AC078846.2, AL356379.10, AC007358.2, AL162231.20, AC000085.5, AC072061.8, AC010234.5, AC007151.2, AL445669.9, AL079340.7, AL445928.8, AC007363.3, Z94056.1, AC012377.5, AC006195.1, AL139109.14, AC002312.1, AC012368.6, AL022164.1, AC027124.4, AC005884.1, AC016574.6, AC010735.11, AL358815.12, AC008009.4, AL109964.20, AL161793.9, AL139092.12, AC010326.6, AC003950.1, AC002351.1, AC022468.5, AE000658.1, AC009484.3, AL031659.9, AC009247.12, AL138836.15, AL121595.5, AC004674.1, AC007386.3, AL355339.7, AC025168.7, AC021188.6, AP001731.1, AL138832.10, AC007228.1, AL355530.6, AJ009612.5, AP001671.1, AC015853.8, AC073607.19, AL137230.3, AL031295.1, AL122125.4, AC018641.3. HADMA77 17 783049 1-1899 15-1913 BE886986, AL118575, BF963505, BE896957, AA019981, AI871227, AW958870, AI148306, AI090074, AA594961, AI620245, N62115, AI499838, BE139496, AA253149, H37934, AW953772, AA398760, BE883579, AW008316, R17479, AI934670, AA253150, AI436173, AI446137, D59581, AI128007, R54297, H42535, D61056, D80139, R61184, AI197892, AA729655, D51488, H55864, H55771, AI075689, AA911710, AA292804, H86756, BF963502, T57670, AI961860, H42534, D51454, D81542, T34704, D80154, D81775, AA001440, T59256, D59479, R42975, R61185, AA994602, D51481, D51437, D59463, D59482, R46039, R51909, AA359928, AA659063, N79566, Z40268, R25021, R42826, D52193, Z42365, AA358058, T57710, AV656695, AL048093, R43779, AW276733, AA365016, AL048094, F01883, AA708838, C14366, N78346, AI601109, W16551, R18081, C00235, BF663261, BC007974.1. HADMB15 18 847116 1-316 15-330 AW136268, BG056888, AI131328, AI174443, AI091646, AW117296, AW168872, AI082447, AI432175, AI290911, AI741489, AI682685, AI142536, BG059892, AW149659, AW071935, AA233541, AI183690, BG056462, AI689641, AA599916, BF196591, BF196843, AA199743, AW136277, N77910, AA564806, AA243035, AA779709, AV722133, AI032138, AA844525, AI467910, AW965361, AA852418, AI982751, AI282445, AI982761, T03902, AI420648, AW167499, H08108, BE328548, AW068986, C15651, D52660, AW665899, AI246702, AI538705, AI271662, AI435112, AI288692, BE466948, AI690048, D55112, AA779042, AL536118, D53747, D54101, AA486941, D53384, W07076, AA232504, AA486765, BF832290, AI038647, AW497637, BF947006, AU155428, T05461, AL136582.1, BC001207.1, AB040527.1, AB058762.1, AB040528.1, AB040529.1. HAGBQ12 19 722205 1-729 15-743 AI332690, AI374724, AI285345, AA876359, AA987498, AI702600, AI079453, AI382918, C04098, R63800, AI697895, H87363, R67068, BE673734, R73892, BF432849, R68633, R68632, R66112, H03322, AA340294, H87907, AP000350.1, AC007363.3, AC003969.1, AC005948.14, AP000360.1, AC004066.1, AC000053.2, AC002060.3, AL450169.1, AL033522.1. HAGCC87 20 638587 1-1578 15-1592 AA587370, AA351604, AA661545, R22639, R22638, R18189, AA650370, AI459585, AI810301, R17880, BF434228, BE811111, BE701381, AA572974, BF857849, T50676, AL120282, AW168846, AI192440, AA714288, AI268019, AI745335, BF681619, BF828236, AU117483, BE147135, AA503298, AW513071, BE675695, AI811846, AI203527, AI079823, AI826761, AA634991, AI355007, AW769654, AI249365, AA704040, AA602951, AA652834, AV762430, W02749, AA836552, AF236698, AA492105, AA747977, AA948670, AI523316, AW337805, AI565126, AI610737, AA405726, AW512528, AI499954, AW013787, AA565232, AI917636, AI869797, AI133083, BG056992, AI887235, AA483075, AI366555, BE906142, AA425924, N33184, AA282951, AA773473, BF868994, AA833896, AA775188, AA251356, AA833875, BF845126, T17332, AW589345, AA736488, AW747980, BE677126, AA713705, AA904211, H91062, BF991881, AW194325, BF447461, BF032064, AL118612, AL034430.4, AL138878.10, AL133332.12, AL117380.28, AL161725.13, AP000143.1, AC004650.1, AL160155.19, AL035086.12, AL512310.3, AL450265.11, AL022393.1, AC004166.12, AC024167.5, AL390918.7, AL135960.1, AJ131016.1, AL035683.9, AF196969.1, AP001695.1, AL049795.20, AC079174.20, AP000090.1, AC002542.1, AC087777.2, AP000893.5, AL365364.19, AL118525.17, AC003962.1, AC004540.1, AL022238.1, AC003665.1, AC005042.1, AC007597.3, D87675.1, AC004662.1, AP001972.4, AP003438.2, AL365223.19, AC010223.5, AC000379.1, AL161670.4, AP001694.1, AC004820.2, AL035594.7, AC004776.1, AC008537.5, AL138759.20, AC002312.1, AL360270.18, AC083884.6, AL031663.2, AC006213.1, AL139322.13, AL356017.3, AC008906.5, AL031726.22, AL355385.15, AC012170.6, AL158147.17, AL138761.12, AL360089.13, AC000085.5, AC079141.7, AL109938.8, AP002847.2, AL512430.14, Z86064.1, AC006511.5, AC055745.23, AL138784.30, AC004987.2, AF168787.1, AC023600.19, AP001718.1, AP000171.1, AP000056.1, AL512658.12, AL031774.1, L78833.1, Z82190.1, AC034186.4, AL031319.5, AP000124.1, AL121902.13, AC012368.6, AL133418.4, AL121997.7, AC005856.1, AL137800.12, AC078961.23, AP001706.1, AL163210.2, AC009996.7, AC026164.5, AL050349.27, AC006251.3, AC020604.9, AC011003.7, AC023510.16, AC005913.2, AJ400879.1, AC007367.3, AL360230.20, AP000330.1, AL132986.4, AL590611.7, AL445489.10, AC026203.3, AL031427.15, AL033378.12, AL031577.1, AC090514.1, AC024093.46, AC026202.6, AC009220.10, AC006455.2, AC005047.3, AL031584.1, AC008685.7, AC006039.2, AC009499.4, AC005091.1, AC005924.2, AL358354.16, AL031123.14, AC002044.1, AC018821.4, AL139274.17, AC013468.12, Y10196.1, AC067941.7, AC010340.7, AC068102.4, AC003108.1, AC006023.2, AC084865.2, AC018686.7, AC006928.15, AC007130.2, AL117330.6, AL031594.9, AL392044.7, AC068724.7, AL450344.4, AL118520.26, AL121929.17, AC073927.9, AC005358.1, AL034346.31, AL445590.4, AP001728.1, AF205588.1, AC022116.5, AP000851.4, AL034372.33, AC005098.2, AP001432.1, AC025540.7, AL357912.10, AC005065.1, Z95116.1, AL139021.6, AL590037.7, AP000462.2, AC007955.4, AP000151.1, AL139125.18, AB017654.1, AL159140.4, AC005343.1, AC090950.1, AC018641.3, AL117337.25, AL034421.7, AL160471.5, AL080243.21, AC022469.5, AL590073.6, AC023114.5, AL031295.1, Z86061.1, AC007458.13, AL163195.5, AL049832.3, AC012519.9, AL022069.1, AL162551.3, AC007005.3, AC004167.1, AL358434.16, AC005099.1, AL138876.23, AC006460.3, AC004477.1, AL445217.3, AP002015.3, AL138958.18, AC004802.1, AC007254.3, AC016579.5, AL391262.3, AC018752.4, AL022329.9, AL133453.3, AP001646.4, AC007270.2, AP000469.2, AL359645.15, AC011246.6, AC003043.1, AC005971.5, AC009032.7, AL353752.6, AC004911.1, AC034207.4, AL356057.12, AC009482.4, AC083868.2, AC007256.5, AC069262.24, AL353741.16, Z98200.8, AP001708.1, AL391839.9, AL118556.4, AL137072.8, AC015971.4, AC010553.6, AC012634.7, AP001717.1, AP000567.2, N55064. HAGFJ67 21 861680 1-2108 15-2122 AW976110, AA214080, AI769673, AW069286, AA722813, AA503101, AI131547, AI378850, AI378385, BE503917, N49844, AI367840, AA443026, AA426172, AW150828, AA453753, AW969343, AL523084, AI335682, AA430073, AA463468, AW016254, AI033532, AA425541, W93005, AI373438, AA454019, AI076112, AA747308, AI471960, Z44094, AI434535, R53526, AA291531, AI280478, W93006, AW016405, R50852, AI081696, AI219348, R35192, AI698625, BE698931, T89701, AW594327, T16616, Z40118, AW865791, AW947328, H01675, W42758, AW466986, AA760631, AI830647, AL523085, H13648, H13649, T89799, W42701, AW969345, AW969483, AW865604, BG113370, AA451809, AV699404, H10264, AV699118, AW938833, AV699156, AV662268, AV725100, AV749106, AV728821, AV662225, AV726109, AF109907.1, AC004846.2. HAGFS57 22 847120 1-860 15-874 BF893958, AL079477, BE221875, AL532698, AI299412, R51649, AL040440, AA339493, F12505, F05649, Z43527, F06606, R12847, BF690787, R25251, T74335, AW382934, AB020663.1. HAGHN57 23 773286 1-2426 15-2440 AL533248, AU118622, AU119331, AU133909, AU119469, AU118182, BE794468, BE791529, BG176702, BE280450, BE729801, BF663566, BF970116, BE257176, BG032912, AL516224, BG121097, BE784191, BG249033, BE727671, BE881192, BE745390, BF792305, BF037862, AV710149, BE617085, AV751361, AW291174, BG163346, AI686123, BG033409, AV762315, AV704873, BE540243, BF344980, AV707943, BF671351, BE394881, AW070780, BE538770, BF303671, BE541947, AW963773, BF303913, AW299817, BE378370, AW299807, BF107096, AW515893, AI338838, BE254836, AW402330, AA455894, AI436127, AL516223, BF001973, AI392820, W31025, W28207, BE535313, BE258523, BF109189, AA182513, BE617702, AW275883, AW674662, BG169977, BE711218, AA134574, AW304388, AA588768, BE868534, AU144819, AA455892, BF802948, BF222585, AW902162, H16095, AI034153, AU145137, AI905391, AI985354, BG011776, AW612879, BE711276, AV659416, AU150558, BE702340, BF055535, BE711244, AA652292, AW271981, AA780056, AI624858, AA319693, AA604113, AV744893, AW771218, AV742941, AA837954, T60588, AA150957, AA151047, AI991761, AI912891, AI628783, AI434787, AW072744, AA716130, BF807693, AA181782, AI554969, AA916968, AA101864, AI473865, AA362607, AW338509, AI525459, BE244147, AI928082, AI433249, BF062859, AI910904, AA285264, BE711295, AI354885, AW006732, AI950274, AU144122, AI990867, AI922170, AA115829, AA806393, BE672240, AU156842, BE243206, AI633602, W01852, BE711219, AI280611, AA707161, AA301320, BF197637, AI695111, AW966603, BF447153, F29695, BE378061, AA336840, AI424341, AA385049, AI307649, N58884, AA131117, AI205138, BF431130, BF807685, N98771, AA602492, BE711204, BF438567, F34557, AA748737, T60437, AA745028, AW891490, AW673414, AI630237, AW378199, AW779341, BE172988, BE172375, AA101187, AA781579, AI478435, BE699167, R57333, AI927982, R92570, BE764834, BF818234, AA648053, BE464290, AK000994.1, AC004668.1, AL050216.1, AA227675. HAGHR18 24 655435 1-1128 15-1142 AA678513. HAJAA47 25 534670 1-1223 15-1237 BF991208, BF743765, AW021917, T74524, T57767, AI491765, N22058, AA904275, AA228349, AI689019, AA054085, AU131834, BE256101, AW270771, AL119691, AI284543, AU118852, BE062478, AI859946, BF769528, AW873261, AW152178, AC009318.11, AL161656.20, AC011811.42, AC018462.4, AL023799.5, AC012170.6, AL137796.6, AP000704.2, AL499628.1, AC007934.7, AC005082.3, AC006111.3, AP001711.1, U91323.1, AC002407.1, AL031680.20, AL356244.12, AL391280.15, AC008526.5, AE006639.1, AC009131.6, AL132987.4, AP000103.1, AL158207.15, AL049540.11, AC013434.8, AP000269.1, AC008755.6, AC008592.4, AL355336.15, AK024933.1, AC090518.2, AE006640.1, AP000212.1, AL133211.9, AC008924.5, AL035422.12, AP000280.2, AC011471.6, AC018719.4, AC005200.1, AC005000.2, AC017079.5, AC004858.2, AL133163.2, AC011472.7, AC009488.5, AF045555.1, AC009756.9, AC007546.5, Z98044.13, AP000107.1, AC008267.6, AC005520.2, Z98050.1, AL121933.15, AC002994.2, AC009137.6, AL133174.15, U47924.1, AP000031.1, AP000354.1, AC011224.8, AL162430.15, AC008450.5, AL021154.1, AC011449.6, AP000039.1, AC000025.2, AC004526.1, AP000355.1, AL356057.12, AL137798.8, AC012085.4, AC004383.1, AC004998.2, AL049713.20, AC005077.5, AC011485.6, AC004253.1, AL449209.2, AP000065.1, AP000134.1, AC008521.5, AP000446.5, AC004477.1, AC022173.7, AL356915.19, AL031432.1, AC026172.3, AP001727.1, AL139415.10, AC012351.3, AC011442.5, AC009412.6, AC005920.1, AL157858.5, AC010271.6, AC010636.6, AL513550.9, AL009183.10, AC020983.7, AL109811.39, AL109797.18, AL022237.1, AC069262.24, AC024078.4, AC004232.1, AC007371.16, AL157882.5, AC011470.5, AC008753.8, AL590762.1, AC005484.2, AF109907.1, AC009155.3, AC004882.2, AL109827.8, AC011452.6, AL121891.22, AL109804.41, AC011465.4, U63721.1, AL357515.26, AL512347.14, AC008738.6, Z81364.1, AC025280.4, AL138878.10, AL050308.9, AL117380.28, AP000471.2, AC002487.1, AL161659.17, AC008764.7, AC005480.3, AC005841.3, AC003070.1, AL022163.1, AJ224877.1, Z93017.6, AC005220.1, AC004821.3, AC005755.1, AC005944.1, AC010319.7, AF157623.1, AJ012824.1, AL353701.15, AL135783.6, AL359236.4, AL122020.5, AL133264.10, AC007366.4, AP001714.1, AL352979.4, U62293.1, AC003959.1, AL359092.14, AC008403.6, AC004968.1, AC011475.6, AC008747.5, AC005409.1, AC027644.9, AC020916.7, AL139353.3, AP001752.1, AL160397.17, AL022312.7, AC005231.2, AC020904.6, AC018663.3, AC010170.3, AL356378.17, AL137073.13, AC005288.1, AL049872.3, AL133405.17, AC008249.14, AC002389.1, AC002492.1, AL139405.11, AL136126.34, AL009179.1, AC073517.5, AC007057.3, AC013356.8, AL137852.15, AL138707.10, AL049775.2, AL135744.4, AC011816.17, AL135752.6, AC007345.5, AC073073.2, AL034402.9, AL160175.5, AJ277546.2, AC020552.4, AC011742.3, AL353777.18, AC008805.7, AL139317.5, AC002301.1, AC010458.5, AC009965.9, AP001719.1, Z98200.8, AC007163.3, AP000167.1, AP000052.1, AC072052.6, Y15994.1, AC002430.1, AL021940.1, Z98752.16. HAJAY92 26 845601 1-2331 15-2345 AI208943. 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BF871314, AI954504, BF753053, AI679312, BE967260, BF207979, AL515195, AW050850, AW089844, AW151136, AL515191, BE965599, AI619607, AI687568, AI540674, AI345688, AL513817, AI590043, BG032036, AA806028, AL043168, AA329665, AI923989, AI670002, AA641818, AI866770, AI679321, AI591420, AI473451, AI445165, AW051088, BF812961, AL514093, AI521560, AI633125, AL514871, AI915291, AW152182, AI247082, AI582932, AI889189, AI587121, BE875959, AA743012, BF814412, AW193894, AL515413, BF911554, AI918449, AF269150.1, AK027788.1, AK000756.1, AF116347.1, AK027438.1, AF160213.1, AF124819.1, BC009311.1, BC001967.1, AB048975.1, AL137478.1, BC002733.1, AB056421.1, AL133560.1, AK027129.1, U42766.1, AL080118.1, BC001969.1, AK026927.1, U38847.1, AB047878.1, AK025857.1, BC004264.1, BC004899.1, AL137529.1, AK000323.1, BC005858.1, M92439.1, AL122100.1, BC006458.1, BC001964.1, AL353956.1, AL137557.1, AF132676.1, AL133640.1, AF061836.1, AL137533.1, AK027164.1, AJ406939.1, AL049430.1, AB056427.1, AK027173.1, BC007571.1, 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X83544.1, BC004290.1, AK026541.1, AF183393.1, AL512746.1, AB051158.1, AF106697.1, AB063071.1, AK000421.1, BC003590.1, AK000257.1, AB060917.1, AF090900.1, BC007680.1, AK027188.1, AL023657.1, AL137292.1, AL133637.1, AL049324.1, S78453.1, BC008416.1, BC008836.1, AJ299431.1, AB047941.1, BC007460.1, AK026613.1, U55017.1, X676881, BC004336.1, AL390139.1, AL110221.1, AF262032.1, BC003602.1, BC002476.1, AL110222.1, AL137521.1, BC006181.1, AL137479.1, BC006807.1. HAQBG57 28 837545 1-1034 15-1048 BE562515, AI742455, AI961996, AA507216, AI190639, AA731364, AI673081, AA593594, AI003558, BF528073, BF885284, AI435334, AW438908, AI381200, R69327, AI204170, AI739035, AI401755, AI591140, AA432147, AA251459, AW967618, AA446655, AI682154, AW613695, AI500259, AA398391, R79970, AI149747, H97579, AI263813, AA401707, BE350370, R69328, AA670245, AA643922, AA852081, BF345349, AA889222, BE782687, BF034010, BF038771, BC008671.1. HARAE26 29 560598 1-1231 15-1245 HATCD80 30 826098 1-1795 15-1809 AW936395, AA382841, BF380111. HBAGD86 31 838799 1-1699 15-1713 AI658681, BE466145, AI806836, AI653272, AA004211, BE302094, BF970406, BE018485, AA418617, AA594901, AI580148, BF589715, AI804211, AI669907, AI342168, AI810310, AA506350, AW022528, H10330, AA721162, AA452114, W03931, AW953290, AI262137, R61309, AA680147, N62384, H10331, AI264925, AA765972, BF086698, AW275301, AA485210, C15277, N79353, AA350799, AI867727, AI474438, AI129224, AA093047, D60782, AI535847, AA897480, AA350798, AV714899, AW956763, AV728867. HBGBC29 32 691473 1-1842 15-1856 BF223021, BF036281, AI341667, AA180986, AU153625, AU151704, AI093197, BE855464, BE018834, BE616741, BF684563, AI694268, AA031711, AI469856, N63041, N50125, AI150599, AI597740, AI985206, AI671591, W72535, BF431270, AI741942, AA037642, AA180865, AA031648, AA436065, AI800796, AA129939, BF056140, AW002265, AU157670, AI074205, AA830493, BF063800, AI056532, AI656721, W00519, AI275143, AI337739, AW172525, AA443349, AA043021, AA446926, AI655558, AI769027, AA101851, AA917703, W93307, AA526333, AI689128, AA777090, AW002829, BE295568, AW139517, AI128702, AI276137, AW801873, AA873711, AW892754, N98234, W76109, AI631104, AA856832, W92810, AA042939, H87505, AA129938, AI688779, AA693329, AI676108, T87624, AA570072, AA037641, AI186390, AW515672, AA031685, AA037500, R82703, AA037234, AW380430, AA985191, AU131994, BE302396, H87506, AA938640, AI926907, AU118291, AI696069, T74071, AA102060, AW057528, AI671894, AI962374, AI695458, AA046964, BE869607, BF814627, F12449, AA725452, AI968837, AA917824, AA054749, BF437316, F10070, AA917678, BE218382, BE669660, AI916503, AW612381, AA683581, AI984598, AA937814, AI932475, AA046963, AA053281, AI801723, BE858841, AI499751, AA031686, AI074981, AI341558, AI478279, BF735972, AK001006.1, BC004523.1, AF020920.1, AF038662.1, AB024436.1, AF022367.1. HBHAA05 33 603174 1-676 15-690 AI572680, AW631267, BF970107, AA632355, AI433952, AI753969, AA629668, AA493546, AU158457, BF589864, AL044966, AW518882, AI570067, AI828721, BF028225, M77888, AI884404, AI547110, BF724416, AI434103, AV683406, AW836225, BE391183, N55076, AA610644, AV731938, AA313025, AA748071, AV743067, AI065031, AW148964, AI280566, AI732690, AA601376, AI311796, AI268465, T03928, AU158814, AW504667, AW880986, AI819419, AA018258, AA524800, AW971342, AI791659, AW020612, AV759022, AV712092, AA935827, AA773560, AA425283, AI376687, AA493245, AA847341, BF942991, BF944618, AW303052, AI174703, BE392753, BG034698, BG223498, BE152006, AI683079, AA826166, AI590404, AI285651, AC004531.1, AL049780.4, AC006013.3, AC005971.5, AC005522.2, AL138713.11, AC011445.6, AC008403.6, AP001725.1, AC010458.5, AC009412.6, AP001726.1, AP001715.1, AL022323.7, AC008569.6, AL138976.5, AC005015.2, AC005081.3, AL022316.2, AC008738.6, AL590762.1, AL445222.9, AC004967.3, AC004991.1, AC020552.4, AP001716.1, AL109965.34, AC006211.1, AC011514.3, AC011485.6, AJ003147.1, AC018755.3, AC011510.7, AC006057.5, AC016995.4, AL353692.14, AC006334.3, Z97054.1, AC006449.19, AC005940.3, AC004383.1, AL034422.24, AC087071.2, AL133229.40, AL079342.17, AC004051.1, AL359397.3, AC018719.4, AP001712.1, AP001724.1, AC020716.3, AC073316.6, AC024561.4, AC010422.7, AC009488.5, AC020908.6, AC000353.27, AL513366.11, AC006487.8, AC020906.6, AC008066.4, AL354735.14, AC006530.4, U95742.1, AL162426.20, AC007731.14, AP000289.1, AL389925.10, AC005500.2, AC002527.1, AP000042.1, AP000110.1, AF001549.1, AL135905.6, AC007637.9, AL161732.7, AC067941.7, Z98941.1, AC032011.14, AP000688.1, AC005377.2, AL050335.32, AC090937.1, AC007256.5, AF053356.1, AC079602.15, AC008623.4, AL163032.3, AC011490.7, AC006040.3, AC004821.3, AC007216.2, AC005881.3, AL133545.10, AC008891.7, AL109825.23, AL138756.23, AL355102.5, AC004703.1, AF312032.1, AL445664.14, AL354696.11, AC005529.7, AC005077.5, AL158207.15, AF168787.1, AC003982.1, AC013449.8, AC021019.5, AC005914.1, AC004032.7, AL158052.10, AL353752.6, AB003151.1, AC005052.2, AC005291.1, AC004867.5, AL023583.25, AC020931.5, AC008752.6, AL023693.25, AC004887.2, AL078639.5, AL031651.33, AC005098.2, AC008551.5, AL136304.10, AL023807.6, AL356756.4, AC005921.3, AC005874.3, AF134471.1, AP001714.1, AC004906.3, AP001748.1, AC004166.12, AC020744.4, AL031118.21, AL139109.14, AC011895.4, AC006312.8, AL049537.48, AC007374.6, AP001630.1, AC007383.4, AC010616.5, AL109797.18, AC006970.6, AC005399.19, AC018711.4, AL020997.1, AC087311.22, AC005632.2, AC005578.1, AC018462.4, AC004522.1, AF243527.1, AC010605.4, AP000563.1, AC026464.6, AP003476.2, AC006511.5, AC004796.2, AC004000.1, AL356113.8, AC011005.7, AP001711.1, AC008857.5, AL138885.21, AC010319.7, AC073347.3, AC002472.6, U52112.1, AP000211.1, AP000133.1, AC009131.6, AC074121.16, AC004263.1, AL449223.7, AJ400877.1, AL161670.4, AC008812.7, AL445071.14, AL117336.22, AC007298.17, AL139343.9, AF207550.1, AL359092.14, AC004963.2, AL096840.25, AC012170.6, AC025593.5, AC022384.4, AL035089.21, AC008969.5, AL355512.22, AP001646.4, AC073542.4, AL359382.23, AC011495.6, AC005562.1, AC002565.1, AL034449.1, AL034549.19, AC008892.5, Z98200.8, AC005102.1, AC012450.9, AC006538.1, AL445483.13, AL354720.14, AC069285.8, AL034548.25, AC002432.1, AC008982.5, AC025166.7, AC005618.1, AL109804.41, AC012085.4, AC008481.7, AC020913.6, AC022432.4, AC005520.2, AC005627.2, AL021395.16, AL117380.28, AC008543.7, AL158824.11, AL109935.39, AL161802.15. HBHAA81 34 846465 1-1633 15-1647 AL138080, AL138081, BG056111, AW117532, AI885223, BF724275, AW051808, AI332809, AI564820, N63569, AW207494, AI866785, AW148811, AI954565, AI199326, AI199105, N38888, AI243422, H09138, AI986175, AW381536, Z25110, AI991904, Z18300, F31192, Z28916, AW381528, Z41646, AI954371, N38887, AI033629, Z28784, AW381480, N94825, F25740, F00372, AW380848, F16581, AW381481, AA197180, AW104762, BF887537, AB042554.1, AB032999.1, AC006059.3. HBJAB02 35 837309 1-1679 15-1693 AL529646, AL529645, BE898304, BG112747, BF791411, BG036058, BE392384, BE621757, BE548173, BE895853, BG034671, AA808894, BE901085, BE278873, AW152607, BE795658, AW166898, BG122141, BE782474, BF972826, BE793716, BE140314, AW750993, AA826362, AW517942, BE714673, T59668, BE731030, BF939314, BE732766, BE745104, AI290469, BF477770, AI805651, AI961329, AA581089, BE902575, AW197375, AA974066, AI950259, BF802171, W27729, AV693783, AA877530, AA715365, AI968889, AA885542, AA160748, AA386371, AA335719, BF873961, W73105, BF223151, BE740826, AL120854, BE548914, AA318192, AA501478, BF125073, AI948815, AA581100, AA658457, AI621069, T59802, AA468534, AA503715, BF850755, AW956069, AW841506, AI144504, AA352215, BE897964, BF883404, BF373009, BE090290, BE168997, AW855521, AW820855, BG230749, BF376598, BE622839, AV699089, AV647789, AI567702, AV726156, AW961037, AW411235, AV726058, AW020397, AV706279, AV702427, AV651955, AV702026, BE393551, AV727787, AV660608, AV687176, AW021717, AV698545, AV687909, AV709256, AV708438, AV656903, AV661704, AV696106, AV697196, AW409775, AW951263, AV689111, AV655280, AV728157, AV692345, AV659322, AV654908, AV656478, AV708893, AV709314, AV708381, AV660728, BG168549, AV659536, AV691080, AY706219, AV695545, AV652001, AV705159, AV648263, AV703169, AV728518, AV707541, AW952409, AV709660, AV726624, AV706854, AV729220, AV709604, AV687035, AV696866, AV728997, AV704955, AV726816, AV725920, AV652156, AV701707, AV656283, AV704234, AV708025, AV707933, AV684604, AV729378, AV708980, AV692691, AV701914, AV708723, AV702516, AV693523, AV709407, AV705693, AV708992, AV729263, AV726103, AV708704, AV727029, AV726520, AV728733, AV725826, AV702021, AV725134, AV705280, AV645906, AV683415, AW265004, AW964228, BE047925, AV705076, AV707792, AV729259, AA127565, AW022102, AV686064, AV701067, AV704124, BC000131.1, AK000069.1, AC015651.18, AF147378.1, AK027463.1, AF097996.1, AF217986.1, AF217994.1, BC000090.1, BC003658.1, BC008282.1, AL356376.9, S71381.1, AK026494.1, BC006378.1, BC004362.1, AL137283.1, AK000212.1, AY026527.1, Y08991.1, BC007199.1, AF218004.1. HBJAC40 36 841235 1-1753 15-1767 BF345048, AW958511, BF530417, BF975837, BE253816, BG250686, BE887472, BF527935, BE263703, BE909332, BF527878, BE881895, BF194837, BF972454, AW025541, AL048612, BF525861, AI859062, BF835934, AI199762, BF955165, AI052782, H12219, BF955173, AW015231, BE379375, AI681619, BF364391, AI379848, AI363268, BF740272, AA703554, R60286, BF955168, R52740, BE258881, AA448130, R90880, W46453, BF090044, R25794, R22673, R52690, H08245, H08001, AA447988, AA912056, AI245669, R36729, AI290546, H07130, M78974, BE179040, T77037, AA070715, H08144, R58852, H38448, Z44633, H49103, W46520, R09542, R85342, AI879032, AI590525, R43378, R90851, T31004, R67310, F13258, BE164925, AA364956, F08103, T32340, BE907755, Z40495, C03430, BF884758, R85671, T35911, T30880, F28188, BF115735, AW161049, AW072139, BF820428, R60889, R60792, AA694126, AI086328, BF961135, AI272235, BE258962, AI363035, F04345, R46793, AA095937, BF952087, F10861, H06622, BF841177, BF925698, AA401578, BF820431, BF945162, BF772214, AA095307, R54673, BE677392, AW027215, AI360330, AF072812, T16940, AL035745, R09655, BF945153, BE081049, BE179106, AA382430, W23297, AW162615, AA946598, AI017807, AI220189, AW002147, R85343, H41244, BF527814, AI863690, AA394215, AW961330, AV652536, AV652547, AW963011, AV654689, AW954779, AW958365, AW954506, AV708498, AW957970, AW950179, AW963847, AV709494, AV725063, AV706850, AV725970, AF131218.1, BC002882.1, AL136698.1, AF195661.1, BC007604.1. HBJCR46 37 815649 1-3194 15-3208 BE980168, BF001800, BF221545, BE180558, BG117357, BG165887, BE747286, BE867206, BE559905, BF029089, BE884542, BE180560, BE882087, BF672818, BE180608, BG255311, BF695020, AI765879, AV701340, AI832097, AV701354, BG164080, BE568492, BF979546, BE268392, BE180559, AI927915, AI675415, BF195785, BF662916, BE673547, AI086866, AI956035, BF671543, AU146956, AA479515, BF063974, W19888, AW992096, BE504075, AW069858, AW992159, AA626631, BE019647, BE221636, AA479513, BF575729, AU144777, AA973047, AA936602, BF671187, BE545703, AV701112, AU144811, AU160319, AI472144, AI263407, BE019684, AU118130, AW614133, AI954073, AI767153, BF445898, AW087744, AI913738, BE397963, AI628089, AI675273, AA447852, AI635143, AW129685, AI287605, AA486193, W00613, AW135604, AI754985, AI334344, BF062454, AW119185, AW576204, BE041839, N54388, BF354864, AI275063, BE175440, AA883965, AI554276, AI082201, BE718001, AW771023, AI274243, AW337565, AA150018, BE175441, AW771580, AA447700, AW052155, AW771203, AA085991, AA085621, AI954014, AW068250, BF725222, AA486299, BF087209, BF834780, AA971016, AW854246, AA150083, H08089, BF735392, BE180609, AV683146, AA677738, AI220075, AV701437, AA740363, AA909807, H71626, R61225, N49411, AV689665, C05160, AA888983, AI026772, AV692963, AW580238, AI816858, AA340276, BE180555, AW862217, R61226, H82142, AW068158, H08090, BF997557, AW862230, AI565387, AI824475, T32511, BE169765, BE002988, AI004624, AW514293, AA775740, T31977, AI660017, AA347780, N63302, AW468684, AA908821, AA953180, AA897589, AI217393, AI536640, AA337664, BF364138, BE816022, AA652646, Z19403, C04239, H71627, AA347779, R14260, AW168255, BF833756, Z42097, AV655482, AI431630, BE088874, BF348891, H82048, AA130053, AA781872, BE544862, Z28501, AI434730, BF575085, AA328725, BF084834, R96217, AU155530, Z38367, AA301061, AA370106, AI810366, AW836437, AA371349, AI991790, H54404, AW015692, Z42140, AI905103, AW242449, BF327421, AI824674, AW195816, BE173133, BF812520, R86231, AI274472, H54488, AW379997, BF476783, D62662, AA382472, AW379945, AL079373, AA703490, AW381290, BF328480, AW392784, AI823416, BF961200, BF910517, BE728262, BE408949, BE277648, AA458950, BF797287, BE866243, AA923063, Z24943, AA236098, BE160734, AA397692, C02287, BF812876, BF444939, AF150734.1, AL136738.1, AK000984.1, AF124434.1, AL033531.10, AL031287.3, AL033532.36, Z97876.1, AC007034.4, AL035304.1. HBJDW56 38 520401 1-623 15-637 AC005532.1, AL031319.5, AL354933.8. HBJEL16 39 847030 1-736 15-750 AI279501, BE867835, AL528252, AA569392, AW856935, AA071326, AA587712, AA258409, AI341817, BE898008, BE696253, AW576885, AA837880, AW576895, AI584147, AL525748, AW383278, AA071368, BF330803, AW383120, AI393286, AL513864, C00710, AW857093, AA644480, AL528253, AW499908, BF326342, AW749039, BF771813, AA193585, AW383268, BG031591, AL040224, AW383242, BE904616, AW751656, AW383266, AW383144, R15553, AW383205, AW383131, BF931485, AA258753, AW383275, AW383146, AW886371, AW997055, AW996855, BE929916, BE005368, AA188924, BF350669, BF327032, Z99943.1, BC007881.1, AL035308.1, AF087020.1, AL035302.1, AF092425.1, AF095727.1, AF092424.1, AF239756.1. HBJFK45 40 531919 1-529 15-543 AA714560. HBJKD16 41 853358 1-1615 15-1629 BG259133, BG258754, BE895955, BE535182, AU119776, BE296370, AW361272, AA205862, BE079707, AI743764, BF669591, BF102652, AA768863, AA767455, AA683506, BF374311, W39021, AA583062, W94893, BE737722, AI128320, AA703242, AA402965, H12229, AA027163, AI338954, W92057, AA769377, AA811137, AW470052, AA027162, AV713020, AI680487, R19758, AA283191, AA531492, AI700367, BF946853, AW514119, AA644413, AI004120, AW876599, BE868122, AI831977, AI219655, AA197283, H17722, AA890197, N70828, AA164346, AV750338, BF791719, AA164345, AA767095, AA393969, AA765421, H17611, BF247968, AI254347, AA253013, AA534905, AA470446, AA182675, H12230, H43795, T32973, AW386765, AU146033, AA078964, R51414, AI269757, T33350, R45177, AI203452, Z44609, AI041094, AV749975, H43709, BF336945, AI268058, T30703, R85203, R51302, R51996, BE738484, W84649, R51995, AA824604, W01425, AA907096, BF801374, BE544754, AI469616, AU156273, AW297202, T83337, H14279, BE929477, AA252973, BE242053, T18899, AA248529, H14306, BE698663, T33352, BG059012, AA361817, AA236020, AA810717, BE243263, AA876139, BF240162, BF893858, BE217859, F13420, H53830, F08935, AA078866, AV727864, AA721692, Z40480, AI383780, H52715, H48241, AW751348, T83485, AI567913, AI247225, BE694869, BE940539, BE713625, BF858355, BF801742, BF824816, BE713728, BE713771, BE713469, AA463921, C01352, AW608887, BE714022, AW876620, AW876628, N89830, BE002346, AA192537, AA319174, BE714013, AV709029, AW991462, AI080442, BF993596, N57976, AA034034, BF799178, BF818732, AW392976, AW876544, BE568245, AW835734, AK000087.1, AK021899.1, AF217983.1, AC008074.3, AK024658.1. HBMUH74 42 866160 1-712 15-726 AI633540, BE999936, AL529110, AI911597, AW016785, AA479308, AI381011, AI057451, AI283542, AI224172, AI025510, BF929951, AW589256, AU156824, AU155569, BF063133, R43074, R25758, BF818086, AL529111, BE567017, BE077233, H09061, AA479409, AL136843.1, AK001927.1, AK027756.1, AK001324.1, AC009318.11. HBQAB79 43 810542 1-1317 15-1331 BE926412, W27043, BG006701, AW500368, AB020689.1. HBXCM66 44 639039 1-996 15-1010 AW970983, AA311432, AA515629, AA515360, AW973992, BF804385, AL046519, AV703785, AA502991, BE968744, AA631507, AI206841, AV763026, AV763058, AW613805, AW340905, AI431303, AI366555, AW873061, AI284640, AW270258, AW341903, AA809546, AI821716, AI613389, AV704541, AI499954, AA533025, AW438542, AL079734, AV655282, AL079645, AL046409, AW023672, N23504, AW419262, AV759632, AI061313, AW872736, AI189682, AV738383, AA533176, AW193265, AW069227, AW023111, BF725844, BE139139, AI284543, AI254770, AW979087, AW026305, AI421950, AI419337, AW872676, AW970981, AL038936, AI634187, AA515351, AV762633, AW327624, AI251034, AI223626, AW407578, AI635440, AI003611, AI801482, AI250552, AI754170, AW574899, AI251284, AI251203, AW130188, AW303196, BF827410, AV755512, AI355559, AV763584, AW845366, AW979241, AI891080, AF123761.1, AP001711.1, AL356805.5, AL122015.17, AC019205.4, AL035249.6, AC009247.12, AP000744.4, AL356214.20, AL356915.19, AL133545.10, AP001725.1, AP000252.1, AL445222.9, AL133453.3, AL117258.4, AB023050.1, AC005077.5, U80017.1, AC012476.8, AC004560.1, AP000557.2, AP000925.5, AC011444.5, AC044797.5, AC005015.2, AL355336.15, AP000212.1, AP000134.1, AC011742.3, AJ003147.1, AC007957.36, AL139022.4, AC018644.6, AC008771.4, AL121936.17, AL390878.6, AL049713.20, AC002527.1, AC004910.1, AC007003.4, AC008012.8, AC022383.3, AC007991.7, AC012170.6, AC023490.5, AC018462.4, AC007270.2, AE006467.1, AC020983.7, AL035420.15, AL136305.14, AC005911.6, AL365505.15, AL137002.19, AC006077.1, AC000353.27, AC011491.5, AC016554.7, AC009068.10, AC016995.4, AC012077.4, AC020934.7, AC007686.5, AC006530.4, AC003098.1, AL356020.3, AC004999.1, AC018695.6, AC011480.3, AC067941.7, AC011479.6, AC009220.10, AD000092.1, AL162390.9, Z81364.1, AP000031.1, AF053356.1, AC026794.4, AC013434.8, AL357497.17, AC025166.7, AJ009613.4, AC005800.1, AB023049.1, AC006121.1, AB003151.1, AC002544.1, AB038653.1, AC009144.5, AC005288.1, AC004841.2, AC004166.12, AP000689.1, AL139322.13, AL023553.5, AC005839.1, AC005731.2, AL121749.13, AC006167.1, AC007318.4, AL353752.6, AL050335.32, AC004965.2, AL022723.4, AL035089.21, AP000556.2, AL021939.1, AC005080.2, AL137230.3, AF165926.2, AC004972.2, AC027126.4, AP001748.1, AC004605.1, AC010620.4, AC010469.7, AL390239.16, AL121893.21, AL353777.18, Z98200.8, AC004033.3, AC084783.2, AL132825.35, AL445483.13, AL118555.6, AL161452.19, AC008555.5, AC010279.4, AL355543.13, AC011461.4, AL391827.18, AL139100.9, AC004912.1, AC008440.8, AC011477.5, AC006483.3, AC010913.9, AP000555.1, AC006443.1, AC004966.2, AC002504.1, Z94802.1, AC007114.7, AL035415.22, AC005921.3, AC008543.7, AL022328.21, AC072052.6, AC010129.3, AC006486.1, AF196972.1, AL133353.6, AL135744.4, AP001752.1, AP001860.2, AL137798.8, AL035588.21, AC087225.1, AP001732.1, AL355343.18, AP000513.1, AL137019.6, AC008736.6, AP002847.2, AC009506.5, AC008747.5, AC006329.5, AC009756.9, AP000511.1, AC011500.7, AL034555.2, AC005037.2, AP003357.2, AC034240.4, Z99716.4, AF200465.1, AC073145.8, AL121580.8, AC007216.2, AL139316.5, AL137792.11, AC090953.1, AC002319.1, AL049569.13, AC018828.3, AC003108.1, AC008775.6, AC005666.1, X53550.1, AC005682.2, AC034193.4, AC009470.4, AC008379.6, AL390241.19, AC018641.3, AJ246003.1, AC018808.4, AF111168.2, AC012627.4, AL022318.2, AL158167.15, AL161670.4, AC004041.1, AL109627.18, AB001523.1, AC020898.5, AL162740.13, AC026202.6, AL136179.15, AL158207.15, AP001760.1, AP002982.2, AC006511.5, AC008040.7, AL021155.1, AL161937.13, AC007546.5, AF077058.1, AC011446.6, AC006153.2, AC004583.1, AL139396.17, AL035587.5, AC008519.4, AL031276.1, AP000553.1, AC025435.5, AL137061.12, AL365444.11, AC005228.1, Z97180.1, AL392166.19, AC008739.5, AC006030.2, AL353668.18, AL033529.25, AP000842.4, AL121972.17, AP000471.2, AC007249.5, AC006111.3, AC004904.1, AC002407.1, AC011811.42, AC003070.1, AC011526.7, AC012076.4, AL161436.12. HBXCX15 45 637542 1-1205 15-1219 AA595781, AW277007, AI274544, AA548746, AC006329.5, AC009412.6. HCDBO32 46 831942 1-2616 15-2630 AL537440, AL531001, AL531000, AU118775, BE613081, AW976126, BE739778, BE612415, BE886668, AW965087, BF671603, BF114976, BF001395, BF104843, BG169691, BF790959, AU145261, AI524826, AV700940, BF115561, AI628083, BE501914, BF028814, BG107506, AA456561, BF695399, BF064237, AW771567, AI554053, AU152051, AI066556, AI478798, BE962627, AW770611, AW963335, BE739003, BF064238, AI801476, AI807830, AA913477, AI424225, AA227589, BF575758, AA625584, AI963182, AW771337, AA576069, AI252762, AA070604, BF589915, AV702872, AA428503, AA235962, AI539101, AA419520, AA721024, BF700344, AI357722, AA314319, AA310761, AA235961, AA888687, AA479915, AW300423, AA304968, AA912243, AI910898, AI521757, AI658537, AI000288, AI244242, AA304963, AI583529, AI950641, AI005178, AI254210, AA806032, BE177264, BE769195, H26906, AI688879, AA832031, AA081596, BF082553, BE699120, BF588478, AW888693, AW888689, AA362983, BE176881, R33476, AI382821, AA614062, AV747748, R34012, AA652453, AV748003, AA343918, AA355362, AW965719, AW819087, AA074345, AC004987.2, AK021702.1, AC004884.1, AB017707.1, AJ012491.1. HCEDR26 47 771144 1-1405 15-1419 AW809560, BF822291, AW805745, T06675, T41328, AW809450, BF884442, BF773357, BF738231, BE163588, BF998055, H00095, BF900030, AA346118, AA644090, BF725844, BF725688, AI919265, AI801505, AW103406, AW855803, BF673854, AA833896, AW958962, AA630854, AI798521, AW855730, AV702109, AA833875, BF725884, AA513851, AW814024, AI537020, AW474825, AW243793, AW275432, AW970064, AC010326.6, AC010645.5, AC010522.3, AL353748.13, AC003006.1, AL136418.4, AL139054.1, AL356805.5, AP000501.1, AP001760.1, AC004840.3, AC007374.6, AL445184.11, AC018738.4, AC008264.10, AC018641.3, AC005102.1, AC007383.4, AC020908.6, AC011497.6, AP000338.2, AC004526.1, AC013356.8, AC011247.10, AL137072.8, AP000216.1, AC006011.2, AC020558.4, AL024498.12, U62293.1, AC004913.2, AC020983.7, AC002044.1, AL355343.18, AC022148.5, AL022316.2, AL354864.16, AL035400.13, AC005529.7, AL109797.18, AC004975.2, AC004895.2, AC002472.6, AP001132.4, AC005881.3, AF258547.1, AC002350.1, AL049776.3, AP002028.1, AC027130.5, AC002558.1, U91321.1, AC008891.7, AC008745.6, AC020913.6, AC004859.2, AF243527.1, AL589723.7, AL031311.1, AC010742.4, L44140.1, AC090950.1, AC026172.3, AL138741.13, AC003048.1, AL137012.6, AC008397.7, AL117352.12, AC005081.3, AL109801.13, AL109798.19, AF258545.2, AL163279.2, AL035587.5, AC010422.7, AC010789.9, AF045555.1, AC011480.3, AC004491.1, AC022217.5, AC011470.5, AP003357.2, AC007283.3, AP001711.1, AC005409.1, AC008812.7, AC008569.6, AF168787.1, AC005082.3, AL158207.15, AL118505.17, AL135927.14, AC007227.3, AC020917.4, Z98949.1, Y14768.1, AC009412.6, AL121992.24, AL117382.28, AC004156.1, AP001694.1, AC007051.3, Z82215.1, AC004796.2, AC073347.3, AC007664.12, AC016776.6, AC020916.7, AP000505.1, AC010328.4, AC004804.1, AC009269.6, AJ400877.1, AF111167.2, AC004167.1, AC007536.9, AC007216.2, AL365364.19, AP001052.1, AL139099.2, AF283320.1, AC009131.6, AL034420.16, AC004755.2, AC000052.16, AC003043.1, AL121891.22, AC002314.1, AC005920.1, AL159977.10, AD001527.1, AL021808.1, AC026464.6, AC005702.1, AL355476.12, AC011455.6, AC009244.24, Z85986.1, Z83844.5, AC004150.8, AL136980.5, AL158823.11, AL158040.13, AL133367.4, AP002392.3, AC000353.27, AC005899.1, AC011489.6, AL035086.12, AC005971.5, AL136087.12, AL445483.13, AL133387.8, AP001752.1, AC009220.10, AC008755.6, AC007993.15, AL138883.12, AL353804.22, AL031767.13, AC009314.4, AC006252.4, AC007666.12, AC019205.4, AL121886.22, AC010320.9, AC009753.5, AC005800.1, AC040160.4, AC004815.2, AL136179.15, AC008536.6, AL096841.6, AC008482.5, AC074142.3, AL109921.21, AC011442.5, AC006333.3, AL158830.17, AC003029.2, AC015982.9, AC012099.4, AL138733.15, AC005412.6, AC027319.5, AC016742.10, AL359092.14, AC012594.7, AL133294.10, AC011005.7, AC007919.18, AL449305.4, AP000744.4, AC005291.1, AC005011.2, AC005098.2, AC009068.10, AL356244.12, AL137230.3, AF235097.1, AL132768.15, Z93015.9, AP001718.1, AC004019.20, AP001720.1, AP001725.1, AC010378.6, AL132640.4, Z82901.1, AL139376.17, AP002852.3, U52111.2, AC002492.1, AC004253.1, AL355353.23, Z82190.1, AL008718.23, AL354932.26, AL031657.5, AL445237.16, AL133448.4, AC007225.2, AL353653.19, AC007390.3, AC008543.7, AC004738.1, AF288742.1, AC006211.1, AC007739.2, AL133545.10, AF111169.2, AL121601.13, AC008474.7, AC004882.2, AC002301.1. HCEEE79 48 560609 1-1038 15-1052 AL353658.33. HCEFG93 49 745400 1-2266 15-2280 AW976010, AW965008, AW342042, AL041706, AL138455, BE061906, BF840676, AW406162, D82290, AW163293, AW574794, AL046205, AW419262, BF311000, AI697208, BE908796, AL135377, AW576391, AW518220, BG222267, BE049095, AI149478, AA720702, AL046898, BF592311, AA493708, AW270270, AI254615, BF592200, AI799642, AA533333, AC018828.3, AC022383.3, AL080243.21, AL590763.1, AC005037.2, AC008403.6, AC004099.1, AC027129.5, AC011236.8, AC007318.4, AC011442.5, AC004966.2, AL031985.10, AP001720.1, AC002365.1, AC010085.3, AL365225.12, AC010289.7, AC018695.6, AL161656.20, AC008755.6, Z83840.7, AC007226.3, AL049709.18, AC011481.4, AE006467.1, AB023054.1, AC024561.4, AC005005.1, AC022384.4, AL360169.17, AC006211.1, AP001694.1, AL157372.18, AC005844.7, AC010654.8, AL445248.7, AL499628.1, AL049795.20, AC012476.8, AP000555.1, AL355312.24, AC008969.5, AC009996.7, AL354872.9, AC073321.4, AJ400879.1, AC011484.4, AC004019.20, AC004867.5, AC006538.1, AC007374.6, AL049712.12, AL160191.2, AC006965.3, L78833.1, AL590762.1, AC087071.2, AL049757.14, AC007707.13, AC025593.5, AL391865.8, AC034193.4, AC067722.21, AL121983.13, AL356915.19, AP001718.1, AC008115.3, AC007151.2, AL132838.4, AL031295.1, AC073657.5, AL035089.21, AC011299.3, AC015801.25, AC018809.4, AC008372.6, AC004382.1, AL354720.14, AC005041.2, AC018808.4, AC011443.6, AC006450.13, AC010792.4, AL031728.12, AC004913.2, AC011461.4, AC004971.3, AL034402.9, Z81364.1, AC010530.7, AL109825.23, AC011470.5, AC004638.1, AL031685.18, AC002316.1, AC003007.1, AL031311.1, AC011475.6, AC004712.1, AC004965.2, AF243527.1, AL391122.9, AC005304.1, AC011489.6, AC018506.4, AL031848.11, AL160269.14, AL133367.4, AL117354.12, AL132768.15, AC069262.24, AL117258.4, AL139316.5, AF001549.1, AL049776.3, AC000052.16, U95742.1, AC006057.5, AC008521.5, AL157938.22, AC018711.4, AL157823.9, AC005077.5, AC004125.1, AL133551.13, AL034420.16, AC010319.7, AC005520.2, AC005280.3, AL354864.16, AC018663.3, AC068799.14, AC005225.2, AC005409.1, AL137230.3, AL445201.14, AC008155.9, AC069282.6, AC004531.1, AL132780.5, AC007130.2, AC004895.2, AC008569.6, AC002350.1, AL137792.11, AL117381.32, AC008745.6, AC008946.6, AC009144.5, AC006312.8, AL355517.12, AC002429.1, AP001972.4, AC005295.1, AC007686.5, AC005034.1, AC007690.11, AP000330.1, AL354735.14, AC005829.1, AC010422.7, AC005335.1, AC003108.1, AP000134.1, AP000212.1, AP000501.1, AL121751.12, Z92846.1, AL391833.10, AC004707.1, AB045361.1, AE006463.1, AC015982.9, AC005940.3, AC006205.7, AL513211.15, AC009131.6, AC022392.4, AC008622.5, AC018841.3, AC009137.6, D87009.1, AL356299.16, AC007298.17, AP002534.1, AC011485.6, AL360230.20, AL031005.1, AC005529.7, AC004089.25, AC006480.3, AC013458.5, AC090527.3, AC006343.2, AP001753.1, AL354928.9, AC007597.3, AF088219.1, AP001690.1, AL121992.24, AL138976.5, AP002851.2, AL136179.15, AC021016.4, AL136123.19, AP001710.1, AC008750.7, AC020983.7, AC007216.2, AL137139.9, AL161731.20, AL157789.6, AL121920.21, AL158040.13, AC011477.5, AC005098.2, AC005089.2, AC004622.1, AP001477.1, AL133477.16. HCEFZ82 50 831745 1-1797 15-1811 BF981465, BF688419, BF969763, BG178653, BE730527, AI672493, N21040, BE395792, AW386160, BE858812, AI672483, BF530193, AI693512, AV751914, BG180158, AI138621, BG104179, AA778387, AA173791, BF939691, AW615384, AW960851, AW594109, BF091657, AI022755, AA209239, AI077708, AI824069, AI936432, AI038303, N39250, AI927782, AI457926, AI436138, AI056772, AI079503, N58793, AI016045, AA210850, AI096581, AA062719, W88815, AA725072, AI375410, AA669791, BE300887, BF431891, AA173843, W31742, W88816, AI740977, BE727603, AI086937, AA704681, AI190844, AI341909, AI365029, N46695, BF590052, AV749863, AI086941, AI676179, AA826493, AA554932, AA789007, BF111593, AA917998, R08679, AA889734, W04647, AA321894, AI912831, AV750240, AI239655, BF592139, H71960, AI368377, AA992261, BE277655, H78240, H78440, AI470391, R37067, AV694383, AI700804, R44781, AW612991, R10835, H96434, N77482, AA314780, R44068, AV751269, R08587, AV697548, AI419628, BE218690, N90646, H65409, BF530646, AA836620, W26811, R10834, AV660888, AV747670, AA905784, AI086303, H84253, AI086248, AV723953, BE881061, BG110517, BE047952, BG180996, AV682466, BF107905, AI312428, BE876038, AW051059, AI538885, AV757598, BF752170, BG113385, BF968903, BG028873, BG113847, AW301865, AL036802, BG033199, AV682875, BG178911, AI345612, AV732936, BF924882, AW827285, BE966634, BG120492, AI345415, AW827206, BG164371, AW827214, AW827276, BF971336, AA568405, BG026714, AL118781, BE965758, BE965192, BE875407, AI581033, AL041573, BG260037, BF835240, AV682330, AI343059, AV760102, BG058150, AI361701, BF816811, AV756838, AI345416, BF338002, AA614183, AI349933, AI340519, AI349937, AI340603, AW129264, AV681885, BE887488, BF341801, AV757639, BE881134, AW022636, AV682787, AV682672, AL036631, BE907151, AL040169, BG034564, BF108279, BG110797, BG029053, AV709517, AA572758, BE966699, AV757018, BE963838, BE875868, BE905726, AW403717, BG114990, BG110660, BG116387, BG036846, BF980991, AI859991, BG119329, BG260187, AV729627, BF915208, AI241901, AW161579, BF911517, AI815232, BE895585, AL036396, BF792050, AI064830, AW673679, BG111377, AV734765, BF814450, AW935969, AW806761, AL045413, AL119836, AI698391, BE536058, BF968533, BE964614, AW302988, AW827289, BF764538, AW778801, AL039086, AV706987, AI433157, BE910005, BE048135, AL513943, AV757943, BE892325, BE965621, BE967307, AI349645, BE874133, BF791952, BG033267, BE965481, BG105812, BF527014, BF816685, AW834302, AI683395, N71199, AV733682, AI312152, BF909758, BC001698.1, AF225418.1, AL133067.1, AL049300.1, AL110196.1, AB055368.1, AL122050.1, AL096744.1, AF090934.1, AL137529.1, AK025958.1, BC006201.1, U42766.1, AL133565.1, AF218031.1, AL136640.1, AK026784.1, AL117457.1, AK026434.1, BC007199.1, AL136787.1, AL389935.1, AL162006.1, S61953.1, AB060908.1, AL136790.1, AF097996.1, BC007926.1, AB062978.1, AF218014.1, AF090900.1, AB047631.1, AB047941.1, AL512733.1, AL050393.1, S78214.1, AL357195.1, AB060929.1, AL133557.1, BC004908.1, AB055303.1, AB060887.1, AF207829.1, AL133080.1, AL133640.1, AF210052.1, BC000090.1, AL359601.1, BC003120.1, AK026518.1, AL137459.1, BC001293.1, AK025015.1, AL035458.35, AF078844.1, AL050116.1, BC003683.1, BC008417.1, AB052200.1, AL442072.1, AK027868.1, AB060229.1, AK026353.1, AB060873.1, AL512746.1, AF111847.1, AL133606.1, AK026542.1, AB056427.1, AK024992.1, BC001967.1, BC004370.1, AL049314.1, AB060837.1, AL050146.1, AL442082.1, AK026506.1, AL137527.1, AB049892.1, AF022813.1, AL049382.1, AB063008.1, AK027161.1, AL359583.1, AK026741.1, AB048974.1, BC006525.1, AK026927.1, AL157431.1, AL162085.1, AF090896.1, AL122121.1, AL162002.1, AK026583.1, AL049430.1, AK026797.1, Z37987.1, AL136789.1, AL133016.1, AK000323.1, AL122118.1, BC006807.1, AL136749.1, AB055361.1, AL137283.1, Y16645.1, AF090943.1, AK026480.1, AF285836.1, AK026522.1, AK026630.1, AK025708.1, AK025484.1, BC008387.1, AB060826.1, AK026086.1, AL133093.1, AB063070.1, AK000432.1, AK025339.1, BC004195.1, AF146568.1, AL137705.1, AL122123.1, BC003104.1, AK000618.1, BC008836.1, AK026855.1, AL136844.1, AB056420.1, AB052191.1, AK025092.1, AL049452.1, AL117460.1, AF090886.1, AF090903.1, AL136845.1, AK024538.1, AL137292.1, AL136799.1, AL512719.1, AB047615.1, AK026744.1, AB056421.1, AL117583.1, AL442083.1, AK024974.1, AK000212.1, AK000083.1, AB056809.1, AL110221.1, BC007680.1, AK026452.1, AB047904.1, AL353956.1, AF056191.1, BC006195.1, AL136784.1, AF104032.1, AF091084.1, AL512750.1, AL512718.1, AK026045.1, AB060863.1, AF125949.1, AL137488.1, AL390167.1, AL080124.1, AL137276.1, AL050277.1, AB048953.1, AL512761.1, AL137271.1, AL359596.1, AB063046.1, AB055366.1, AF120268.1, AJ242859.1, AK025632.1, AL080127.1, AB049758.1, AK026924.1, AL137550.1, U72621.3, BC001418.2, AK024594.1, AB051158.1, BC006440.1, AL049283.1, Y10936.1, AK025375.1, AK025414.1, AK025573.1, AB060852.1, AL512689.1, AL122100.1, AL583915.1, AL110225.1, AL136892.1, AY034001.1, AK026600.1, D83032.1, BC007021.1, BC003687.1, AB047878.1, AL136884.1, BC008488.1, Y14040.1, BC002839.1, AL389983.1, BC008899.1, AK000137.1, AL049466.1, AK026959.1, AB048954.1, AB063088.1, AL136893.1, BC008282.1, BC004119.1, AL136586.1, AF090901.1, AL122093.1, BC008893.1, AB060214.1, AL096751.1, BC008365.1, AL080060.1, AK027113.1, AB060912.1, AL162083.1, AL136767.1, AL049938.1, AL512684.1, BC002647.1, AK000445.1, BC006408.1, AF069506.1, AK025084.1, BC007556.1, AL133075.1, BC003548.1, AL137533.1, BC008078.1, AL136864.1, AL137548.1, AF106862.1, BC006832.1, AK026591.1, AL133560.1, AK000652.1. HCFLN88 51 610000 1-1420 15-1434 AL526786, BE622815, BE746913, BG167566, BE612603, BE613343, BE543099, AW328570, AI084727, AW511229, BE879597, AA643500, AI090381, BE876617, AW055002, AI744096, AA714840, AI148138, AA598703, AW340721, BE559510, AI125728, AI830384, AU151986, AI885716, BF432640, AI475597, AW339888, AI377299, AI309247, AW005497, AW771450, BE622365, AI139390, AI422379, N95665, AI144110, BF341713, AI919264, AI475648, AI189926, BF809564, AI559248, BE396630, AI817016, AI640708, AA825735, AV662025, BF526593, AI708507, AA935563, AW939178, AW939138, AW939190, AA961207, N66071, N69365, AA603786, AW939128, AI285062, AI826293, AW951255, BF512843, AA620317, AW605529, N80991, AI285338, AW381729, BF956527, AI031873, AW381749, BG056758, AW371517, AW381756, R78288, AI434319, AI282698, AI343784, AW002119, AW169595, N48713, AW371499, AI537993, N26561, R52366, AI916353, R93746, BE828699, AA835499, AW072300, W70306, AA907306, AW748173, N68294, AI468129, BG032430, H89920, AI080137, AA326474, H69097, AA826574, AW303330, AI858652, AI804227, AA322294, AI342977, AA291513, N35677, AI824463, T86711, H49562, Z19236, AI500205, AW966976, AI187820, R78289, AL525884, W76006, BE828722, N81088, F37932, R31642, AA905077, AA922535, AA877249, BF957167, AA780926, BG055657, AW087260, AI202070, AW129497, AA911554, AA045568, R32359, AA204681, AA057054, AA364763, R63145, AI277392, AI886719, BE616036, AW238934, AI082383, BG164867, BG150873, BE548567, BG035187, N91393, BF957863, H69096, R88359, AW328569, BF743483, BF742356, BC001967.1, BC000956.2, AC005089.2, X89985.1, AJ223979.1. HCHAB84 52 834326 1-1345 15-1359 X84712, BF526942, BF036429, BF035689, BF034330, BE878646, BG117306, BE906856, BE871642, AV703538, AW955111, BE729985, BE958344, BE271782, BF698225, BE568321, BG250080, BF826293, BE156569, AW579884, BF977502, AA587630, BE621946, BF512422, BF695706, AV764128, AA448786, AI032411, AA477231, BF695587, AA641139, BE621432, H02682, H02590, H29948, AW972521, AA186733, BF909586, R22544, BE673152, AW405966, AI358557, R22543, BG169787, BF813006, BF742389, AW673871, AA327923, AW392393, AA311766, BF916201, BF742334, R70413, AV763358, AA505606, AA477230, AW794624, AW674083, AA595661, AA579044, AW265468, AA807704, AA642809, AW021674, AA618263, AA405570, BG180320, AA533066, AI702049, AI061313, AI254267, AA084439, AA491767, BG059139, AL042667, AL042670, AA187682, AV763460, BF131490, AA313025, AL121039, AA557945, AW148821, BF901147, AW402784, AA693484, AV758870, AW410844, AW873417, AA601376, AL119909, AI251024, AI444575, BF725761, AW963489, BF857486, AI141202, AA776665, AW069110, AA601290, AW469462, AW270385, AI572680, AW028376, BF817511, AA809116, BF739035, AI064968, AA640310, AA535216, AI679759, AI753113, BF030482, AA600863, AI185160, AW192930, AL138262, BG118544, AW675677, AW023390, AW672927, R67038, AI445699, AI312267, AA659832, AV647070, BF804385, AA610644, AI821901, AV764383, AW105463, BF770715, R83577, AU157209, AI039257, AA602906, AA809546, AW820105, AA502991, AV762112, AI252611, AI567676, AI476049, AA015948, AF126023.1, AF126024.1, BC005943.1, U02057.1, AC002492.1, AL365364.19, AP001760.1, Z68276.1, AC008649.6, AC007842.1, AL157823.9, AL162587.20, AP001711.1, AC021752.5, AC007405.6, AP000133.1, AP000211.1, AC090514.1, AC004922.2, AC013449.8, AL034451.26, AC008891.7, AC020659.5, AL139039.17, AF168787.1, AC010463.6, AC003102.1, AL139353.3, AC006261.1, AC009756.9, AC008946.6, AP000563.1, AC002310.1, AC008068.4, U47924.1, Z69719.1, AL050349.27, AC003048.1, AL359983.7, AC009412.6, AL391839.9, AL031846.2, AL121655.1, Z95331.2, AL389875.1, AC005207.1, AC020716.3, AC009137.6, AP000252.1, AC026172.3, AC006111.3, AP001692.1, AC007333.6, AC005821.1, AB038653.1, AL035684.25, AC005081.3, AC008745.6, AL136300.22, AC005902.7, AC073073.2, AL034418.5, AJ295844.1, AL139317.5, AC020904.6, AF139813.1, AC005519.3, AL445483.13, AP003357.2, AC087239.18, AL049869.6, AC020906.6, AC025280.4, L78810.1, AC008567.4, Z83844.5, AC008821.5, AC009220.10, AC073898.1, AC009311.3, AC004542.1, AC002306.1, AL031311.1, AC016683.7, AL158207.15, AC023105.7, AC006449.19, AL139100.9, AC016594.6, AL356805.5, AC008044.4, AL133517.11, AL133541.21, AC016763.8, AC002554.1, AL020993.1, AC008403.6, AC005355.1, AL121675.36, AL359695.6, AC005261.1, AL163032.3, AL513550.9, AP000511.1, AL589677.6, AC026464.6, AL096712.20, AC024561.4, AC011448.3, AL117348.25, AC010627.5, AC073657.5, AC005288.1, AC010271.6, AP001745.1, AL135783.6, AC090950.1, AF334404.1, AC007055.3, AC008771.4, L44140.1, AL031427.15, AC010319.7, AC007637.9, AL158158.14, AL035086.12, AL451125.7, AC018711.4, AC012085.4, AL135752.6, AC009247.12, Z84466.1, AF053356.1, AC008009.4, AC025165.27, AL133211.9, AL158830.17, AC002551.1, AL109984.14, AC002477.1, AL159168.15, AF205588.1, AC007383.4, AP000146.1, AC010491.3, AC006483.3, AE000658.1, AC004883.2, AC025264.16, AL133230.25, AC007390.3, AF042090.1, AL035455.30, AC005280.3, AC008897.7, AC069255.18, AC011495.6, AC005038.5, AC005914.1, AL136228.8, AP001709.1, AC022211.5, AL139113.21, Z97181.1, AL022323.7, AL137244.28, AE006462.1, Z98048.1, AL133453.3, AF111168.2, AC083884.6, AC010422.7, AP001630.1, AC010458.5, AL353716.18, AL109935.39, AL139316.5, Z94160.1, AC008857.5, AL157372.18, AP002007.4, AC005080.2, AC005412.6, AC008481.7, AC009123.6, AP000356.1, AL137787.11, AC004854.2, AL121886.22, AL133375.25, AC003684.1, AP002392.3, AL121594.6, AC027319.5, AC026185.3, AC005759.1, AC004263.1, AC020552.4, AC032011.14, AC004686.1, AL049636.22, AC007957.36, AJ243213.1, AL139343.9, AC091394.2, AL117381.32, AL163636.6, AC005527.3, AC008521.5, AP002427.3, AL354932.26, AC011891.3, AL138836.15, AC005529.7, AC004975.2, AL442166.1, AB023048.1, AC008555.5, AC011445.6, AC005781.1, AC080011.21, AL121712.27, AC020934.7, AC008372.6, AL031587.3, AL121601.13, AL133355.12, AC026445.4, Z84488.1, AL050347.1, AL161747.5, AP000744.4, AC083876.2, AL359236.4, AL133448.4, AL163284.2, AC008543.7, AC007255.4, AL096701.14, AC010203.13, AL157818.12, AL133312.3, AC005180.2, AC010620.4, AF038458.1, AC004659.1, AC007277.2, AC000353.27. HCLBK61 53 845659 1-1574 15-1588 AW888225, BE909010, BG179776, BG035454, BG110521, AW961918, AL046940, AW886511, BE257058, BG028046, AV704518, AV707665, AA115296, BE778760, BF968134, BG118898, AA127752, AV709320, AA482432, BF844844, AI719551, AA115271, AV706611, AA292209, AA127675, AI754750, AI817764, AI084658, AI921925, BF215850, AI480051, BG028121, AI720847, AI936895, AV704680, BF844824, AI978596, AI973004, AV706575, BE315319, BF930346, BF675963, AI754633, W39064, N25471, AA927727, BF667059, AA482579, BF593800, AI142422, N94401, AI423383, AA452021, BE810269, AA009997, BF204826, R58555, AA890468, W29031, AA575879, AI096965, BF058738, BF038338, AA988949, AA894599, BE881224, AI050691, AW378187, AI139378, H63931, AV749480, AI678930, AI086800, N27892, BE272725, AV746711, BF793328, AI081394, AI359024, BF130110, AA399442, AA429791, AI378588, AI051332, BE176746, AW043773, AA772301, AW771084, AA700495, N33460, AA984550, AA911305, AW378172, AI125344, AI949335, W03369, AI300324, AI270397, AI344414, AI337951, AI278254, AA558222, BF726680, AA861332, N20819, AI193787, AI084108, AA916406, AI902353, W04346, AA425936, AA643567, W76634, N30542, AA938581, AA428805, AI497697, AI057222, BF351642, C03717, AI147178, BF845000, AA028054, AA412390, W30996, W69873, AL523500, BF449052, AA470118, AV713038, AA425645, AA047051, AI344638, H83544, BF059077, AA532699, N42433, N32467, H28269, H63932, BF726505, W21922, AA702306, BF432294, AI873123, H77909, N21060, AA577542, BF798936, H28220, AI085350, AA503903, AA740273, AA659072, AI168251, AA039609, BG152771, R96127, BF434642, AI359034, T36061, N67698, AI568058, AA494013, N27140, AA421453, AA009998, AW337863, T53377, BF763474, AW005163, AI873124, AA326544, AA421485, H63529, AA960770, AA531176, AA856783, BF752804, AV751492, BF948183, H63530, AA348414, BF092572, AI095810, H85295, BE767177, AA580353, AI217059, N40077, BE706846, H52470, BF832678, AA463191, AA558171, AA463190, R01193, AA373286, AA635123, T94569, H29968, H29872, BF751352, BF764314, BF765576, AI669786, H52471, AA830715, BF752791, R77247, N89808, AA844445, AA317712, AI332804, BF056933, BF764311, AL523501, R55436, BF929262, AW243538, BF092554, H54201, T32427, AA757759, AI803744, AA463278, AA355008, BF678579, AA768259, AA724652, H84289, AA330278, BF196615, BE706366, H85448, AA361590, BG011029, AW664707, AA319575, R01305, Z25103, AA301933, T56761, AA384049, BF813459, N56549, AA861336, T94259, BF752233, BF752225, AC009299.5, AC005837.1, T53378, T56762, T93294, T93970, R54987, R77248, H06183, H11502, H11862, H84831, H85339, H84970, H85729, H85822, H86001, N40893, N74180, N98765, W73027, W93909, AA018728, AA019282, AA035257, AA064779, AA083961, AA112160, AA129076, AA129077, AA234327, AA262998, AA583602, AA715448, N56021, N56477, N86983, C03990, AA028053, AA704666, AA718987, AI025994, Z28779, Z43917. HCMSX51 54 788643 1-2239 15-2253 AL520206, AL522291, AL520207, BG115714, BG023953, BF343959, AU133571, BE839880, AW954438, BE264316, BG261277, BE879757, AU131026, BE265959, BE278903, BF725639, AW246741, AA864833, AU148856, BF111640, AA706935, AA431813, N38742, BE857705, BF476344, AU152863, AU125122, AA480041, AW170367, AI094797, AU154528, N48379, BF913004, N26479, AI803158, AL120744, N35219, AW245159, AI089912, AI927351, N20323, AL046695, AA476664, N35530, AI078494, AA015687, AI016568, BE857202, AI587317, AA446620, AW629254, AI433184, AA548282, W03412, N27597, W00855, AA825427, AI128747, AI082265, H38927, BF970202, R48359, AI569253, N29410, N44883, AW014479, AA934555, N41471, AW974179, R15948, AA573084, AA233832, AA017058, W16680, AI312737, R60804, N67483, R15949, Z43237, BE811896, N45053, BE832888, T11764, Z43099, AA431409, R48260, AI933045, AW874096, AW105691, AA336676, AA044969, BF362640, AW893387, AW892550, AW892516, R60299, N35043, T49574, Z41630, AA013473, N35211, AA738419, AA223632, H86402, T49573, AA017209, BF941569, AA635071, AA054652, H86066, AI351292, F02575, N79527, T11765, T35773, AW993110, AW194575, BE893541, AA448030, AI086309, BF737533, AF001690.1, AF029231.1, U96629.1, AB007042.1, AB011091.1, T66574, T66575. HCNCO11 55 775086 1-732 15-746 BF926420, BF926408, BF875996, AV705104, AV726755, AW964429, AW950395, AV703435, AV707451, AV707628, AW961373, AV705453, AW964210, AW964423, AV704361, AW952896, AW961510, AV726887, AV729165, AW963643, AV707705, AW963965, AV707556, AV702814, AW963219, AV704916, AV706906, AV703045, AW950229, AV690921, AV704674, AV728297, AV702810, AW960535, AI557262, AW963644, AV708024, AV701594, AV727806, AV727803, AW957298, AV650843, AW957682, AV704283, AV708829, AV701751, AW950078, AW950079, AW949946, AW961329, AW954386, AW954962, AW957974, AW952228, AV725024, AW960663, AW957083, AW950256, AV649266, AV704144, AV703160, AW963857, AW966775, AW958568, AW964298, AW958569, AW966684, AW951998, AV704342, AV703361, AV704848, AV703833, AV703425, AV705771, AV653846, AV728884, AW960406, AW954104, AW945153, AV650865, AV705189, AW958320, AW958316, AV729457, AV728929, AV729285, AV726743, AW949454, AW953619, AW955397, AW949863, AV701787, AW945196, AV708035, AV702901, AW961052, AV701953, AW963108, AV729170, AW958127, AV703284, AV706964, AV728355, AW963612, D50992, AV703367, AV706742, AV703862, AV706047, AV709139, AV652860, AW955394, AV702749, AV708590, AV707020, AW951793, AW951816, AW967188, AV705481, AV706133, AV702435, AV702958, AW955616, AW954194, AW962970, AV726728, AV705420, AV726770, AV695489, AV691061, AW963234, AW955139, AV649942, AW962367, AW964203, AW954242, AW954413, AV727101, AV707189, AW966146, AW951740, AW960600, AW952132, AV703632, AW961431, AW964278, AW958290, AW959722, AV659467, AV706802, AV705998, AV709332, AV705516, AV728913, AV728341, AV709281, AW958045, AW950597, AV707266, AW950411, AW960545, AV705267, AV704712, AV704401, AV702819, AV702458, AV702187, AW965827, AV727386, AW949731, AV707117, AV702298, AV701626, AV727268, AV703465, AW954783, AW953992, AW963581, AW958104, AW950254, AV705154, AW962980, AW957286, AW962378, AW958093, AW963811, AW954221, AV727618, AW963652, AV652536, AW962929, AV704033, AW950520, AW952361, AV701614, AV705518, AV728428, AV729392, AV702035, AV709623, AV702315, AV703266, AV707197, AW945183, AV727756, AV707238, AV706910, AW961377, AW945164, AW950681, AV647033, AV647066, AV647129, AW957628, AW952419, AV707649, AW957779, AV647144, AV702975, D59751, AV650924, AV693604, AW960143, AW963486, AV704876, AV705321, AV652547, AV650877, AW955698, AV707907, AW956167, AW963667, AV703264, AW963401, AV653784, AV727589, AW963641, AW955697, AW955632, AW955629, AV728741, AW961403, AW949521, U94592.1, Z30183.1. HCNSD29 56 862314 1-1714 15-1728 AU130793, AA902780, BG114197, AA675900, BE548792, BE796388, Z78308, BF973800, BF125408, BF382619, BF894864, AA902842, AW083941, BF243278, AW131275, AA155995, AW771771, AA938206, BE251257, AI745367, AA448317, AW511804, AA448455, AI370549, BE139488, AW176079, AA156223, H73833, BF940408, H73162, AW084204, BF062122, AW028149, BF924722, BF433518, AI263130, AA411961, AW071942, BF694503, AA743704, AV764156, BF948901, AW082575, R11580, AA412712, BG153595, BG058948, BF893682, AU130757, BF667868, AF049523.1, BC000273.1, AF049528.1, AK024810.1, U70667.1, AF049524.1, AK023109.1, R34683, R34788, R63327, R63326, R63340, R63341, H15969, H27538, H27547, H27621, H82731, H83344, H83606, H83696, N20620, N32195, N33798, N36103, N36549, N41405, N41578, N44109, W19354, W25310, W38906, W60991, W73124, N89856, AA027859, AA027925, AA034908, AA034975, AA133603, AA133602, AA172294, AA261835, AA262483, AA523928, AA551549, AA563835, AA857095, AA872771, AI095007, AI096629, C05812, C15709, AA247765, AA393650, AA400834, AA487693, AA488710, AA663750, Z21548, AA843596, AA844473, AI041193, AI083985, Z41640, Z46025, Z44537, F03607, D11797, AI262317, AI264408, AI304594. HCQBH72 57 637548 1-1782 15-1796 HCQCC96 58 845066 1-2152 15-2166 BF970581, BG117166, AV695085, AV686338, AI341460, AW173384, AV693976, BF032394, BG024316, BE893802, BG254562, AW055235, W39204, BG170478, AW978735, BF572731, AW968956, AI909118, AI909124, AW592429, BG171038, AW118938, AI689438, AI419443, AI801242, AW438695, AI123971, N59864, AA707755, AA974210, AW130020, AA489046, AA768780, AI146982, AW768627, AI093766, AW889585, AW298736, BF111650, AA284319, AA907244, AW874520, AI535676, AW579265, AI955386, AA279581, AA983814, BF185409, BE622718, N59886, AI859864, AI498376, BG171039, BG116650, W01363, AI699807, AA824487, T86598, AA994605, AW044013, T85108, AA489144, AW768600, AA811658, AW271482, BE895361, AI631722, AW021293, R64514, T77523, AA736753, H44608, AI955411, AV689519, N90263, AL119283, H94626, T77559, AL119309, T86597, AI909117, AW376940, N79005, N77027, AW105078, N62828, AI701272, AI334730, T07505, AW848643, AW243861, AI909110, BG007292, BE162291, BE162293, AA532611, AP001816.2, AL022153.1, AC004804.1, AC015982.9, AC006840.17. HCUDD64 59 835082 1-388 15-402 BF109963, AI870761, AI149403, BE675981, AI979111, AI590348, AI769440, AA568609, F04371, R68556, N24429, R85927, AW973928, W02539, BG150863, R79201, N69412, R79466, T80848, AI494453, R28549, AW440020, AL390151.1. HCWAE64 60 535893 1-457 15-471 AL043265, BE895962, BF091850, BF924502, BF930204, AW973724, BE906549, BF972009, AA558125, BG163769, AW993087. HDPCW16 61 840358 1-1522 15-1536 AL046424, AL520269, AL530345, AL520270, AL525169, BF337231, BG118238, BE798545, AW246567, BF970663, BF965787, BF969366, BE783929, BE793384, BE266986, BF528633, BF347353, AL525170, AI815776, BF344880, BF792135, AW793516, BE263579, AW297948, AW296357, BG059919, BF968412, BE261945, AW364801, BE070095, AW516100, AI859217, AI205184, BE350228, AW245703, AW248385, AW008242, AI674610, AA450134, AA677778, AW191853, AW083410, AI973282, BF155249, AI500208, AI359204, BF961380, AI571182, AA593565, BG025370, AW194193, AI214035, AV698756, AI659973, H17114, AA225572, AW245580, AW247948, AW954225, AA861285, BF745614, AI927559, BE265979, AA775443, AW015750, H18943, AA642634, BF836642, AW732061, AA665550, AA678588, AI817267, D60749, AI674941, AF009759, H74159, D60750, Z40715, AI698885, AA564889, AA687090, AA225658, AA468959, D51256, AI435027, T91353, BF593487, AI520908, AI597773, AI865553, AI694877, AI041194, AW135397, R12563, H17219, AA777103, BF834394, AA337430, AA694470, BF916766, BG111049, AI872869, AI572751, AI927445, D81096, AI342344, T30521, T91440, T30520, AA662525, AW149871, AI312176, T30121, AA090561, T15863, AI985606, AI053516, N88658, AI566726, R09913, R62464, AA339338, AA523081, AW961065, BF222090, AA927388, AW874224, AA558682, AA478552, BF111253, BF855358, BF209274, BF677966, M78952, T32904, BF957728, AW059622, BE746763, AL047548, AF108658.1, AL050118.1, AC004228.2, AF084559.1, AK027459.1, AK027577.1, AK027513.1, AF126799.1, AF139813.1, AC004770.1. HDPDI72 62 897277 1-1536 15-1550 AV717810, AC018828.3, AC011464.5, AC022383.3, AC022384.4, AC034193.4, AC002472.6, AC021015.4, AC008119.6, AL356299.16, AC004951.5, AC018808.4, AF003626.1, AP000215.1. HDPGE24 63 801947 1-2611 15-2625 BE876192, AU145980, BE839859, AW953709, AV651029, AW866434, AW866436, AW866430, AV687299, AA604920, AA604512, AI887664, AW813014, BE839866, AA164729, AI566037, AA602341, AA602613, AA214047, BE839860, AI355441, AW855356, AA506540, AU119708, AW855353, AI884345, AV656490, AI049591, AW853687, AW995969, AI963674, BG058784, BF681462, BE811870, AA551394, BE081412, BE672638, AV687875, BE564307, AW935217, BE811892, BE145548, BE563924, AW577107, AV704081, AA631460, AW380640, AA366464, BG012149, BF694965, AW341886, AW866268, AI537997, F29519, AI537504, AI567884, BF874935, AV659506, AW363563, AA631500, AI363970, AA669020, AI270484, H78415, BE709511, AA640505, BE178526, AI989765, AW866337, AW953693, AA484751, AA342969, BF882965, AA484783, AV659374, BE796439, AV695480, AV659391, AW024055, AV659405, AI832956, T81440, AA654981, R70506, BF852810, AA484906, AW997573, AW379425, AI932609, AA631380, AA570339, BE708328, AI597820, BF694852, BE815355, AW934969, AW902128, AV684943, AA366571, BG260565, AA632800, AW007894, AW192258, AI886084, AV764490, H82763, AW131401, T69164, AA605054, AW573583, AA834697, AW858120, AW893702, AW573573, AW074527, AV714931, AW820698, AI679343, AA558871, BF853927, AW438596, BF883928, Z32833, AA503427, AW393438, AA610678, AA522988, AA483882, R95100, AW893701, T59151, AW965008, AA848158, BE067011, T98359, T68422, AI679520, BF935516, AA528276, BE839943, BE929829, AL120269, AV759172, H02561, AV760701, AW802714, BE541237, N21656, AI457389, BE066950, T30343, AI679960, H78215, AV700663, AW978714, AL135377, AA243867, AW151713, AW102955, BF884208, AW157616, BF846275, BG034591, BF106210, BG011353, AA161288, BF883454, AC000353.27, AF001893.1, AC006121.1, AC005484.2, AP001710.1, AL590762.1, AC009961.11, AL035555.10, AL160411.25, Z83822.1, AC022402.4, AL136139.6, AC005291.1, AC007225.2, AC007021.3, AC018828.3, AC010742.4, AL391259.15, AC090943.1, AC090514.1, Z98946.15, AL450263.15, AL034372.33, AC008873.4, AP002812.3, AF224669.1, AC006030.2, AL031311.1, AL122020.5, AL049759.10, AL117692.5, Z94801.1, AC008670.4, AL022318.2, AC008892.5, AC027124.4, AP000555.1, AP001169.1, AC018502.5, AC002378.1, AL390074.17, AC083863.2, AC066597.4, AC002091.1, AC079141.7, Z94056.1, AC005157.1, AL354720.14, AC026391.6, AP001715.1, AC040160.4, AL139109.14, Z97054.1, AC002289.1, AC007450.1, AC007482.7, AE000658.1, AL499604.9, Z84484.1, AP001724.1, AL109865.36, AC066608.5, AC073101.7, AC007850.29, AL137139.9, AL079342.17, AC018642.6, AC007773.1, AC024163.2, AL162231.20, AC007097.4, AL035685.21, AP000352.2, AL021368.1, AF111167.2, AC007363.3, AF088219.1, AC004125.1, AC009137.6, AC018755.3, AL158828.14, AC026398.4, AL356652.19, AC005846.1, AC023510.16, AL355096.4, AC034240.4, AL049713.20, AC011742.3, AL163853.4, AC015982.9, AL138743.5, AC007907.2, AC091492.1, AC021188.6, AC018682.4, AL138878.10, AL390025.1, AC006050.1, AB026898.1, AC011236.8, AC004024.2, AC005214.1, AC002464.1, AL139113.21, AC005046.3, AP000246.1, AP000207.1, AC007563.2, AC005520.2, AL137128.4, AL031670.6, AL442167.1, AL163285.2, AC011816.17, AC024166.3, AC011739.7, AC013734.4, AL021154.1, AC005881.3, AC005697.1, AL022165.1, AL391114.12, AL023513.1, Z98044.13, AC000094.3, AP000129.1, AL139415.10, AC011242.8, Z98304.1, AL589693.3, AL391122.9, AL445435.11, AC003071.1, AF131216.1, AL360272.23, AC087071.2, AC003962.1, AL136123.19, AC020908.6, AP001830.4, AC008450.5, AL445669.9, AJ271736.1, AL034550.31, AL118557.5, AC008891.7, AP000782.3, AP000500.1, AC011464.5, AC011311.11, AL158196.24, AC025262.27, AL049869.6, Z93341.5, AC022468.5, Z92542.2, AL034384.1, AP001728.1, AL031387.4, AC002994.2, AL591807.1, AC022407.6, AL160231.4, AC007065.5, AC005539.1, AL050318.13, U91322.1, AL133415.12, AC010252.3, AC068781.18, AL133500.3, AC008011.11, AJ400877.1, AL390738.4, AC044797.5, AC006445.11, AP000688.1, AL445071.14, AL133545.10, AL035089.21, Z98884.11, AL355535.14, AC007999.12, AC022007.3, AC083871.2, AP000350.1, AL354696.11, U80017.1, AP001671.1, AL121997.7, AC007282.4, AL139330.17, AL049779.6, AL163282.2, U82671.3, AL445928.8, AP001412.2, AC022392.4, AJ400879.1, AL161454.10, AC090957.1, AP001922.4, AC003091.1, AC005971.5, AL121905.23, AL161935.10, AC022267.8, AL158141.14, AC025165.27, AL158198.14, AL160036.12, AL136303.15, AC004707.1, AC012450.9, AF131215.1, AL132657.33, AC006965.3, AL161937.13, AC005969.4, AC018633.2, AC004764.1, AL359846.11, AL118556.4, AF196970.1, AL137787.11, AL360169.17, AC018769.2, AC000052.16, AF190464.1, AL137100.4, AL445248.7, AC008738.6, AC018523.9, AC005670.1, AC010605.4, AC007541.9, AL049795.20, AL096712.20, AC006057.5, AC004019.20, AC006071.1, AC026166.4, AL132640.4, AC022201.4, AC008569.6, AC003049.1, Z84469.1. HDPIE44 64 899328 1-4101 15-4115 AL528314, AU130887, BE780963, BF966718, AL118570, BE739397, AU126476, AU139315, BF512830, BG115027, BE880693, AI908306, BF791388, BF035925, BF540985, AU122664, AV724420, AI672418, BF665031, BF057158, BF206660, BG120429, BE738855, BF129883, AW959181, BF106186, BF966523, BF213412, AI042351, BF211302, AL042137, BF515714, BF206917, BF031857, BF131974, BF129874, BE514139, AV696443, BF037314, AV661523, AW130577, AA424461, AW130565, AA902916, AU127429, BF677116, AU150429, BF665735, AA983275, AI239435, BE155330, AV705068, BF212900, AV710135, BF432386, BF057834, BF211687, AA461260, AA312396, AI627321, AI160503, N63373, BE502195, AV751301, AI884925, BE468064, BF513143, AV750990, AA186321, BF184200, BE559625, AA749086, AW025721, AU152756, AI418879, AA402517, N26419, AA088855, AI042350, BE268734, AI761107, AI819134, AA678020, AU150014, AA113363, AW341372, BF184441, AI457727, AA649198, BE674349, AA888970, AA580858, AA199866, BE270920, AV649723, H24854, AA100701, AW025691, BE836719, BG010680, BE550985, BE087003, AA326555, R77878, AA424417, AA188173, AL044709, H05951, BF792719, BF930036, N56631, N41679, BF923482, H45855, AI218982, AW779309, AV751002, BE089649, C17343, BF081703, R81295, AA502426, BE646243, BE931964, AW594429, BE676875, R11716, BF748564, H06000, AA460953, BE832883, AV703744, AI265945, AV751157, BE720186, AW021533, T09412, BF849176, AA088766, AA437111, AA336899, BE262777, AA358792, BE155518, H99315, BG166471, BE270762, BE313275, BF239379, AA888732, BE825194, T89695, D78877, AI269641, BG011279, AI469067, AW874055, AW338714, AW874611, N88500, BF445639, AW058314, BE677169, AW139207, R17691, T31819, AW513547, AW472793, AA358708, AV660383, AI765491, AI582998, AI084965, AA598573, AV750235, AA730781, R44452, D61165, AA716555, AA056000, AA322246, R08530, AA333655, BE972774, BE169279, AI870585, BE615699, AI870612, BE169269, AI678506, AI640581, AA648833, R08529, BE383572, BE247425, BF155632, R19666, AW993917, D62489, BG028138, AL040103, AA360932, AI763357, AI652881, BF088332, BE327501, AL528313, AA055971, AV749018, AV748843, AA088700, AI570710, AA004833, AI685231, AA178900, AI886543, BE812475, AW166705, BE812487, T89515, AA347000, D60417, BE937678, AW054783, BE812457, T48558, AA953749, AI199099, AI769397, AI369907, AA199752, BE701083, BF914380, BF508221, BE838996, BE707763, AV646433, BE819207, AV651409, T25765, AA113444, AB018353.1, AK022816.1, AK025737.1, AF202724.1, AK022469.1, AF064854.1, AL133074.1, AA188877. HDPIU94 65 813352 1-2182 15-2196 AU140297, AL529544, AL529545, AU124978, AI740820, AU116885, AU126162, AW960772, AI565169, BF111956, BG251247, BG177689, BE780814, AI628285, AA482031, BE784432, AA947029, AW954823, AW190175, AA315300, AU143854, AA707674, AI332610, N50136, AU148736, AU127152, AW768480, BF947113, AA223261, AW955931, AI276839, AA189165, AA804584, AA767472, AA223378, AA894857, AA252718, R46372, AA939277, N59367, AA219127, AA774827, AV762911, BE546354, N72682, AA219510, AV761697, AA872005, AW188325, W02461, R21326, AI923716, D29223, R68368, BF771937, BE769443, AA322537, R08745, AA417592, R08746, AW952240, AA299861, AW377015, AA337351, H60482, N76470, BF088734, AA218745, AA336556, BE896274, AI810734, AW118290, BF380800, T30177, D29202, BF910258, AA337527, AA336555, R68574, AI167609, AA376922, AW968355, BF351657, AI832198, AW972092, AW968356, AW972093, AW968729, AI432644, AI623302, AW971740, AI432654, AI432650, AI432653, AW081103, AW858522, AW972091, AW969229, BE672759, AW972090, AI432677, AI431230, AI431307, AI431316, AI431328, AI431353, AI431312, AI432655, AI431310, AW128900, AI431238, AL045327, AI431354, AI432666, AA580821, AI431347, AI431315, BF448552, BE672748, AI432661, AL134524, AI431323, AI431337, AI432675, AI431321, AI492519, BE672745, BE672732, AI431246, BE672719, U46344, AI431235, AI431243, AI432647, AI432651, BE672738, AI431255, AI432674, AI431330, AI432649, BE672767, AI791349, AW601637, AI431248, AI431241, AL042842, AI431254, BE672774, AI431357, AL042729, AI432672, AI432665, BE672742, AL042931, BF589777, AI432662, BE672627, AW577201, AI431345, BE672644, AL042655, AI431351, AL042508, AI431231, AI431346, AL042853, AI432676, AI432673, AI432658, AW128884, AI431257, AW577199, AL042533, AL043166, AL047611, AI431340, AL135012, BE672622, BE672792, AI432657, AL042802, AW128846, AI431247, AI432664, AI432645, BE672718, AL042787, AL042515, AL042832, AI431751, AL043295, AI431314, AI492520, BE672634, BE672743, AI355008, AI492510, AL042898, AI431350, AL043091, AI431318, BE883591, BG167830, BE672749, BE672744, AI682915, AL040207, AW128897, AI866786, AW129223, AL042488, AI432643, AL043278, AK022626.1, BC001240.1, AK001284.1, AF064854.1, AL133074.1, AL133053.1, AL136763.1, AL133049.1, AL133076.1, AL122101.1, AL136755.1, AL136758.1, AL133068.1, AL136825.1, AL133051.1. HDPIY31 66 886159 1-1964 15-1978 AL533296, AU142272, BE560264, BG117407, BE407326, BG116397, BE314927, BE315405, BF205715, AI935180, BE313422, AW965613, BF315382, AI701496, BF727272, BF115518, AI829152, AW474694, H23483, AL040572, AI005000, AA311926, BE297986, AI298282, BE743406, AI675622, AW845300, BF306252, AA037364, AI097581, BF308743, BE296105, AW148771, AI339720, AA455474, BE670969, H23486, T66744, BE818161, R17317, AI268300, AW070382, AI291626, AW409641, AA834030, AI880154, R17812, R13082, AA324613, H23484, T27067, H86644, BF892771, R46701, AA349448, R20964, AA923102, H05150, H23485, T87222, N77062, Z43932, H23020, AW136846, AI742491, AI372678, T16039, T66743, AI372676, R45314, BF681190, H08379, AW864486, AA732753, BE312682, AW864516, H29561, R22677, AA324777, AA774961, R25545, F10589, AI523364, AA379005, T26481, BF904678, Z39993, H06774, H24087, AA670426, R20154, Z42195, R44466, R18635, F07975, Z44889, R59906, AI560142, R53460, R43016, R20237, AI745398, BF904916, H24300, R41995, R53461, H06899, AW801037, T74057, F07778, H08380, AA323177, BF763326, M85501, F12373, BF689358, H08954, R44142, F04562, F01724, F04134, F04226, T15999, AA037520, AA677085, BF335984, R40512, R20492, AL533261, BF858775, R56265, R13207, AA987631, T34814, R42746, BE747609, F09993, AA099781, R63798, R43692, AA902512, AA455473, R55721, F04028, AI984376, AI243094, AA776086, BE504276, BE155765, T10103, Z38178, T16439, BF851177, T10102, BF851176, T16686, BF335999, F01506, BF851173, BE818200, R14040, BF851221, BE814269, BF851178, BE327839, H06858, AW003241, BE394938, BE393786, BF851170, BF884029, H13338, BF858389, AA234656, AW748209, AI393102, R47781, R50313, R50305, AA976743, BF851229, BF335998, AV727501, BG165051, AA323766, AI758272, BG163618, BG113299, AI922707, BG164558, BF037292, BF341801, AV746964, BF792961, BG030364, AA643623, AI702406, BF970449, AW827289, BF921103, BE895585, AW827227, AW827206, AI471361, AW050578, AW196105, BG249582, AV682575, BG108406, AL036736, BE138658, AI345608, BE620202, AI431909, AI345471, AI805769, AI308032, BG027280, AI344785, AL041772, AI452993, AL134999, BG260037, AW983691, AW071417, AI924686, BF753056, BG112718, AI608936, AI963216, AW082594, AI335426, AI348777, BE965355, BF885000, AV735098, AI620284, R40432, AI269580, AI886124, BF814541, AI802833, AW302992, AI812015, BF343099, BF793644, AI799195, AI824576, AW168031, AL118506.27, AK023132.1, AK024508.1, AL137301.1, AK026542.1, AL389982.1, AK024538.1, AL359596.1, AF260566.1, AL137550.1, AL442072.1, BC008417.1, AL359615.1, BC003687.1, AK000432.1, BC004370.1, AL117585.1, AB063070.1, AK000647.1, BC008365.1, AF146568.1, AK026784.1, AF003737.1, AB055366.1, AB063084.1, AL110221.1, AK026462.1, AL110225.1, AL136892.1, AK027164.1, AK025967.1, AK026528.1, BC008280.1, AK027204.1, AB019565.1, AL359618.1, AK026629.1, AK025391.1, AL122050.1, AB050510.1, BC002733.1, AB060916.1, AL359941.1, AF217966.1, AL512754.1, AL117460.1, AK025798.1, AB055303.1, AB060887.1, AL136799.1, AF061943.1, AF078844.1, AK024524.1, AL136928.1, AB051158.1, BC008070.1, AF090943.1, BC005151.1, AF225424.1, AJ012755.1, AL080060.1, BC008382.1, AL137271.1, AB056421.1, AL117583.1, AK000083.1, AB060929.1, AL050277.1, BC003548.1, AK026534.1, AF056191.1, AL136805.1, AL512718.1, AF026816.2, AL137556.1, AL049452.1, BC006164.1, AL137560.1, AK026045.1, AB055374.1, S78214.1, AL133557.1, AK026593.1, AL049382.1, AF271350.1, S61953.1, AF090934.1, AK026526.1, AL390154.1, BC001967.1, AK027116.1, AF177336.1, Z82022.1, AF183393.1, AK026630.1, AL389939.1, BC003684.1, AF090896.1, AK026551.1, AL110280.1, AF091084.1, BC007326.1, AF097996.1, BC002839.1, BC008899.1, AK026959.1, AB060863.1, AB063046.1, AL137459.1, AB048954.1, AK027213.1, BC001045.1, AB052200.1, AF125948.1, AL442082.1, AL136845.1, AL122093.1, AB060214.1, BC007199.1, U42766.1, AK026408.1, X72889.1, BC008780.1, AL137526.1, AL512719.1, AB055361.1, AK026762.1, AB060825.1, AL136768.1, AL583915.1, AK025484.1, AL353956.1, AL133565.1, AL512750.1, BC003683.1, AF113222.1, AK026532.1, AL133104.1, AB052191.1, BC009033.1, AK026504.1, AK027096.1, AB048953.1, AF162270.1, AF218014.1, AL136786.1, U39656.1, AB056427.1, AB063008.1, BC006440.1 X69819.1, BC004951.1, AK025414.1, AK027193.1, AL049464.1, AL137538.1, AK000486.1, AL136843.1, AL359601.1, AB055368.1, AK026927.1, BC007198.1, AF111847.1, AL353940.1, U80742.1, AL117394.1, AB056768.1, BC006412.1, BC009341.1, AL137480.1, AL136749.1, AK000618.1, AK026464.1, AB050534.1, AL133067.1, Y16645.1, AL137557.1, AL110196.1, AK000445.1, AB047615.1, AK026642.1, AK025906.1, AK000137.1, AK026947.1, AK025491.1, BC004958.1, AB063079.1, AK025573.1, AB060839.1, AF207829.1, AK025312.1, AL359623.1, AK025524.1, AK025772.1, AL117440.1, AK000391.1, AF090901.1, AL050393.1, X65873.1, BC008983.1, BC006525.1, AK026647.1, AB048964.1, AL080074.1, AK026353.1, AB047904.1, AL049314.1, AL137648.1, AB056420.1, AJ242859.1, BC001963.1, AB060852.1, AL512689.1, AF219137.1, AL050149.1, AF125949.1, AL050146.1, AL136864.1, AL359620.1, BC008488.1, AL050138.1, AL122123.1, AL162002.1, AL122049.1, AB060826.1, AL049300.1, BC005890.1, AK026086.1, AK026480.1, AB062942.1, AB060908.1, AL512733.1, BC006807.1, AL122098.1, AL117457.1, AK026855.1, AL136787.1, BC005678.1, AL080137.1, BC008387.1, BC003122.1, AL117435.1, AK026744.1, AL136844.1, AK026608.1, AL080127.1, AL136789.1, AL162062.1, AF090900.1, AL133016.1. HDPOC24 67 777493 1-1763 15-1777 BE795755, BE799575, BF346049, BE736856, BE735839, BE613439, BE295320, BG165897, BG028052, BE904063, BF525670, BG248216, AI762392, BE798809, BE876262, BE538403, BE541775, BE278995, BE867896, AI928014, BE735450, BE792862, AI302814, AI417544, AI861926, BE868781, AI620234, AI949339, AW292331, AA425932, AI635177, AA716408, BE964527, AI148619, AI188537, AI751315, AW298424, AI570424, BE019043, AI333093, BE563878, BG166956, AI679326, AI339585, BE208614, AI912361, AI199939, AI638579, BF035843, AA575835, AW562325, AW167212, AA613113, AJ403125, BE300704, BG230624, AA631882, AA654351, AI188665, AI744337, AI042080, AA554771, BF205494, AI751314, AI357368, N42873, AI623763, BE205782, BG015408, BF061667, AW296851, N73029, BE548655, AI080401, AI200653, AI346327, AI804793, AA723378, AI219032, AI923960, AW512977, AI334021, BF739379, AI961597, AI933388, AW118019, AI750231, H49782, AW516158, W73379, AI682039, AW068519, AI199855, AI858410, AW275973, AW338079, AA856546, AW071218, AA428801, AI128328, AW026790, BE673142, AW513049, AA582918, BG056078, AA936754, AW513987, AA579898, AW192791, R55015, R80153, BF197452, AI738833, AU157028, AW627680, R62188, BG152556, AW516091, BG057769, AI538819, AW085840, AI500700, AW082065, BE614205, N34466, C75025, R55153, AW630976, R81484, AI687198, BE271478, AA975810, AI207300, BG253177, H13762, BE463629, H13709, AA983929, T97913, AI719056, AI203064, R80154, AI074832, AW104721, R47833, AA852278, AA812419, AA088385, R64576, AI362616, AW068781, W73403, R21634, AA553687, BE544315, D31024, W44598, BF346027, N33449, AA573257, AA857087, R49975, AI915025, AI382413, BF847025, R54690, AW591357, AW953807, N53663, BF752914, AA469380, AA469299, BF111939, AW301188, N50673, AW270044, BE549470, BE540690, AI673113, AI380538, AA364267, W39364, AW572002, AW080124, R81724, N42422, BE785221, D20947, BE966528, W44617, BF829622, W38340, AA948112, BE074077, AL137555.1, AK025951.1, AK025804.1, BC001979.1, AL445222.9, AF151783.1, AK023580.1. HDPPD93 68 637588 1-687 15-701 AI767544, BF963878, AW391604, AW371053, AW391605, AW380560, BE150935, AW380557, AW609397, AV647627, AW609527, AV647628, BE150882, AA625481, AV647780, AW582425, AW582423, AA053357, Z39028, T31703, AI559952, AI962812, AW023035, AW247321, AW594578, AW204377, AW135110, AW069029, AA737065, R51075, AW294433, AW291912, BF511819, AW292027, AI265783, BF063801, AI274716, AI191509, AA605269, AI768872, BF057534, AI634812, AI698531, AA565825, AI275563, AI366661, BE242780, AI538787, AI203337, AI565080, AW008059, AW088320, AW073352, W73510, AW242351, AI341846, BF222967, AA513453, AI346467, AA622940, AI000935, AA535424, AI022694, BF592958, AA639759, AI679288, AI679864, AI079193, AU147451, N56986, AU148991, AI304785, AA134162, AW664542, AI337342, AI245649, AI969305, AW582354, AI081970, AI262353, AL079933, AW976197, AI991639, BF349821, AU159502, AW004865, AA665733, AI348128, AI094163, AI184073, AU152120, AU149126, AI359191, BE552234, AA632288, AA814449, AW362622, AU159545, N75380, N49596, BF869959, H48051, N70679, BF987335, AI864296, AA928727, BE963530, AA617935, AI151119, BF680667, AW978110, BE785995, BF913501, AL519088, H56669, BF526020, AI668893, AV655645, AV714752, AW087445, AW104724, AI538716, AL045500, AI564719, AI802542, BG058398, AW026882, BG031815, AI433157, BG179993, BF812961, AI620284, AI524671, AI857296, AI619502, AW118557, AI682841, AI439745, AI934035, AL514129, AL036274, AL036361, BG111590, AI560099, BE048071, BG260037, AI445432, AL036802, BG257535, AV732936, BF970449, BF812938, BG110517, AA640779, AI536685, AI445025, BG180996, AL514983, AL121365, AI521012, AI537677, BE884130, AI475371, BG112718, BG113299, AI702406, BG110684, AI349004, AI580984, AI687127, AL513907, BF032868, AW166970, AI687375, AI625079, AI440239, AI349645, AI635461, AL119049, AI433976, AW071349, AV753074, AV757018, AI285735, AV758209, BG109270, AI271786, BF792961, AI498579, BF882343, AI281762, AI690480, AI815855, BG170430, AI783504, AL043975, AI636456, AI687728, AV682093, AV708097, AW302988, AI432969, AW148716, AI800384, BG112879, BF924882, AI697137, AL514879, AL036396, AL048656, AI500077, AW827211, AI282655, AI962456, AW268253, AV681618, AV756619, AW086113, BF793244, AW129659, BF885675, AV758822, BF816811, AV758592, AI799470, AI539780, AI828682, AV681869, AI610307, AI612913, AW132056, AI872711, AI818683, AI499393, AI493248, BE887488, AV713079, AV652906, AI340519, AI537303, AW071417, AI475451, AL040243, BF107577, AW082040, AL036146, BF038106, BG036846, BF726297, AV682849, AK026796.1, AK027770.1, AL391244.11, AF251294.1, AL136882.1, AK022241.1, AB051496.1, AK026647.1, BC008387.1, BC006195.1, AF090903.1, AB055361.1, AL117394.1, BC008488.1, AB060826.1, AB063070.1, S78214.1, AL117457.1, AK025339.1, AK025092.1, AF125948.1, AB060912.1, AL359615.1, AL133606.1, AL122050.1, AL049452.1, AL157431.1, BC001967.1, AL049314.1, AL162006.1, AL137459.1, AL512746.1, AL050149.1, AK025958.1, AB055303.1, AB060887.1, AL050116.1, AL110225.1, AB048953.1, AB056420.1, AL050277.1, AL512733.1, BC008365.1, AF106862.1, BC008417.1, AL442082.1, AL117435.1, AK027096.1, AL136749.1, AL133640.1, AL133016.1, BC003687.1, AL136586.1, AL136787.1, AF090934.1, AK025084.1, AK026855.1, AL136789.1, AL512719.1, AL137557.1, AL110196.1, AK026741.1, AL359601.1, AB049758.1, AF090901.1, AL050393.1, AF104032.1, AL162083.1, AK026959.1, AK000083.1, AL133075.1, AL050108.1, AF225424.1, AF090900.1, AL389982.1, BC007021.1, AK026592.1, AK026865.1, AL122121.1, AL122123.1, AK000137.1, AL117460.1, AL110221.1, AL050146.1, AF090943.1, AL133080.1, AF219137.1, AK026045.1, AL359596.1, AK026452.1, AL096744.1, AF090896.1, AB060863.1, AB063046.1, AK000618.1, AL080124.1, AL359941.1, AF218014.1, AL512754.1, AL512718.1, AB060916.1, AL049938.1, AL133093.1, AK024538.1, AL049466.1, AF078844.1, AL136892.1, U42766.1, AK027868.1, AK026608.1, AB048954.1, AK026784.1, AL133560.1, AL390167.1, AB055368.1, AB055315.1, AB019565.1, AL080060.1, AL122093.1, AL133565.1, BC003683.1, Y16645.1, AB048964.1, AL389978.1, BC006807.1, AB063008.1, AJ242859.1, AF125949.1, AF111847.1, AL442072.1, AB056768.1, AL137527.1, AL359618.1, AK026744.1, AF146568.1, AK000445.1, AB060825.1, AK025772.1, BC007199.1, U91329.1, AF091084.1, AK025906.1, AL136844.1, AB051158.1, AB047615.1, AL117583.1, AB047801.1, AK026534.1, AL136799.1, AK026542.1, AL353940.1, BC004556.1, BC002733.1, BC008899.1, AK025491.1, AL133557.1, AL136768.1, X82434.1, BC001045.1, AL117585.1, AK000323.1, AL049464.1, AK027113.1, AK026504.1, AF207829.1, AB060908.1, AK000212.1, AB062938.1, AL050138.1, AK000432.1, AK026583.1, BC004951.1, AB055366.1, AK026927.1, AL080137.1, AK000652.1, AB052200.1, AL137550.1, AK025391.1, AK026353.1, AK026532.1, AL049300.1, AK025967.1, AL050024.1, AB060852.1, AL137283.1, AL122098.1, AF097996.1, AL512689.1, AL136928.1, AL049382.1, AK026533.1, AK025414.1, AK026528.1, AB056809.1, AB047904.1, AL136786.1, AB052191.1, BC008070.1, AL136845.1, BC002839.1, AL049430.1, AK000614.1, AF260566.1, AL133113.1, AB056421.1, AK026086.1, AL137271.1, AF177336.1, AK027204.1, BC008485.1, AK027164.1, AF183393.1, AK024588.1, AK024524.1, Z82022.1, AK026947.1, AL122110.1, BC008382.1, AK026526.1, AL512761.1, AL137648.1, AL137463.1, AL049283.1, AK026630.1, AK025484.1, AF271350.1, BC008983.1, AK026480.1, AL359583.1, X72889.1, AK027116.1, AK027213.1, AK026629.1, AB060929.1, AK025524.1, AB050510.1, AK025209.1, AK000647.1, AL512765.1, AK026597.1, AL512684.1, BC003548.1, AL137538.1, AK026642.1, AK000718.1, AL359622.1, AL080127.1. HDPPQ30 69 684292 1-1049 15-1063 AL041375, BE140949, BE077105, BF880881, AA809125, AW177869, AI890297, AW338376, AA171400, BE328286, AA218684, AV683406, AI310670, AW902110, AA489390, AI523205, AI792092, AI760835, AI821056, AI821805, AI801563, AW901945, AA526542, AW902135, BF876674, AI819419, AW022796, AA084320, AI254267, AW504667, AW162314, BF530611, AA661583, AA515727, AA935827, AI521525, H62123, AW265006, AW021674, AA324108, AI609992, BF812696, AI174703, BG231195, AI310787, AI280535, AA720582, AI753904, AI984168, AA584493, AI349130, AW169183, AI609984, AW264548, BE245594, AI797998, AW020150, AW238341, AI568376, AI610012, AI572680, AI278440, AI277373, AA232928, AW020094, BE676856, AI609974, AA425283, AI224583, AW192419, F23338, AI926102, AW162332, AA555232, AW104161, AA804726, AW021399, BE676988, AA525753, AW971320, BF882222, AA167656, BF949151, AA689351, AA584241, AL044701, AW511778, AA557945, AW265468, AW328446, BG180320, AA568303, AA493546, AA807684, AA280886, AW855527, AI889995, BE063437, BE154909, AA568311, AI345566, AA599712, AW275432, BF870762, AA810158, AA182928, R23873, AA492496, BF904892, AI815583, AW674277, AI816537, AA636077, BE244308, AA595661, AW084445, AA657808, AW510403, BG152746, BF800073, AW962791, AA180056, AW243817, AA604601, F29968, AI344906, AI318548, AW085626, AI369076, AI860423, BF681222, AA610381, AV759517, AI915081, AW157128, R73744, AW571716, BF448553, AW303052, AA507623, AW129188, AV763650, AA703818, AL042667, AL042670, AA493808, AI733523, AA679946, AA578711, AW576299, R92703, AA347203, AW072963, AV706458, AW152439, BF792474, BF061241, AV764119, AI567676, H05066, AL022315.1, AC005531.1, AC005080.2, AC011475.6, AC008372.6, AC020626.6, AP001630.1, D28126.1, AL137073.13, AL590762.1, AC011444.5, AL034548.25, AP001748.1, AC004967.3, AP001717.1, AL354932.26, AC006121.1, AL034377.1, AL356299.16, AC002126.1, AC012476.8, AC002544.1, AC007172.6, AP000359.1, AL137787.11, AC021016.4, U91326.1, AC007934.7, AC018751.30, AC009516.19, AC008736.6, AL354873.19, AC009996.7, X62355.1, AC005996.2, Z93241.11, AL031729.16, AC006071.1, Z68285.2, AC008745.6, AC010789.9, AL121652.2, AL049569.13, AL133507.8, AF053356.1, AC005052.2, AL022316.2, AC020897.6, AC008403.6, AC008379.6, AL121653.2, AC008569.6, AJ277557.1, AC027319.5, AC083866.2, AL008718.23, AC004755.2, AP000045.1, AL031666.6, AC005933.1, AC026464.6, AC005632.2, AL136162.17, AF207550.1, AL031255.1, AL050335.32, AC009123.6, AC011005.7, AL109923.29, AC000360.35, AP000553.1, AC008392.6, AC005913.2, AL121992.24, AL162426.20, AC009314.4, AL158823.11, AC005412.6, AP000346.1, AL121989.12, AC008397.7, AL137012.6, AC021396.6, AL499628.1, AC002352.1, L35532.1, AL138784.30, AC010422.7, AC005695.1, AL359092.14, AC011533.6, AC072052.6, AC008543.7, AC008427.7, AC002425.1, AF001548.1, AC007956.5, AC024561.4, Z95113.2, AC003982.1, AL034422.24, AL135927.14, AC007227.3, AL355512.22, AF243527.1, AL589723.7, AL157838.24, AC005696.1, AL136084.11, AL445248.7, AC004790.1, AC011495.6, AC005098.2, AC005754.1, AL035684.25, AF190464.1, AP000501.1, AC004228.2, AL035405.10, AC005856.1, AC006011.2, AC004884.1, AC008753.8, AL391647.16, AF051976.2, AC005180.2, AL023583.25, AL136418.4, AL139054.1, AC011455.6, AP003352.2, AC020908.6, AC005071.2, AC008666.5, AL080243.21, AC005874.3, AL109653.14, AF134471.1, AC027130.5, AC009412.6, AC007969.3, AC005015.2, AL513008.14, AC018690.5, AL117338.15, Z93928.1, AP000345.1, AL096763.14, AC004878.2, AL121601.13, AL139389.16, AC025436.2, AC002477.1, L47222.1, Z97056.1, AL133163.2, AC003110.1, AC005488.2, AL136117.12, AC002302.1, AC004081.1, AC008812.7, AC009131.6, AC026765.22, AL353706.6, AL392084.6, AL121656.2, AC068724.7, AP001711.1, AL050343.17, AF254983.2, AL512883.5, AF134726.1, AL158850.8, AP001725.1, AL357515.26, AC008755.6, AC010463.6, AC004144.1, AL133211.9, AC009086.5, AC068499.1, AL161747.5, AC007201.1, AP001883.5, AC004802.1, AC008651.7, AC010792.4, AC004867.5, AP000512.1, AC005060.3, AL031847.17, AC007003.4, AC008892.5, AC011442.5, Z97632.1, AC011994.10, AC005940.3, AC004882.2, AL034423.21, AC003007.1, AL049776.3, AC006026.2, AC002416.1, AP002456.3, Z83844.5, AL139339.22, AL137139.9, AC006162.1, AC008545.3, AP001710.1, AC004655.1, AF023268.1, AL121983.13, AP000252.1, AC008536.6, AL137791.19, AL035588.21, AC004643.1, AL356747.18, AC009309.4, AC005779.1, AC004883.2, AL353597.20, AL445071.14, AC004826.3, AP001705.1, AC005533.2, AP000793.5, AP000031.1, AL008582.11, AL049760.26, AC020906.6, AB020878.1, AF003626.1, AC084865.2, AL133367.4, AL359983.7, AC004816.1, AL163201.2, AC020558.4, AC008752.6, AC004020.1, AL161669.5, AL358777.12, AL121897.32, AC009244.24, AL133448.4, AC010319.7, AP000689.1. HDQHM36 70 852328 1-1533 15-1547 AA287570, AA255853, AI361900, AV763026, AV763058, BG164602, BF965394, AW105346, BG164455, AI570805, AW088846, AI754653, AA600202, AC003962.1, AC005081.3, AC018809.4, AL035658.7, AC007957.36, AC009060.7, AL109984.14, AL590762.1, AL133477.16, AC004671.1, AC000134.14, AC002288.1, AC005488.2, AC006483.3, AC011895.4, AC024561.4, AL121928.13, AL022476.2, AC005531.1, AC005332.1, AC010311.8, AL096841.6, AC011475.6, AC002310.1, AC004686.1, AL050318.13, AC004965.2, AC008440.8, AC020904.6, AC011491.5, AP000555.1, AC013355.7, AC004985.2, AC016587.7, AC009412.6, AP000557.2, AC019205.4, AL139150.12, AC005919.1, AC011495.6, AC005231.2, AC087071.2, AC009228.4, AC021036.5, AC010605.4, Z83822.1, L78833.1, AL049872.3, AL122035.6, D87675.1, ALA45184.11, AF053356.1, AC022007.3, AC006120.1, AC005911.6, AC005280.3, AL157938.22, AC020931.5, Z85986.1, AC010530.7, AC005015.2, AL022326.1, AL080243.21, AC009123.6, AC015801.25, AC007216.2, AC083866.2, AC027319.5, AC004477.1, AC020916.7, AC004408.1, AL034549.19, AP000558.1, AL035072.16, AE006462.1, AL121655.1, AL139331.19, AL391827.18, AC020917.4, AL133387.8, AC002316.1, AL109825.23, AL451075.15, AP001717.1, AL121845.20, AL139317.5, AC005940.3, AC005702.1, AC009516.19, AC005971.5, AB023049.1, AC004812.1, AD000092.1, AL159191.4, AC009756.9, AC008805.7, AC008403.6, AL121897.32, AL022328.21, AC008962.8, AC009131.6, AL121753.30, AF045555.1, AC008569.6, AC009144.5, AC011485.6, AL359091.10, AC005098.2, AC005071.2, AC011811.42, AC009247.12, Z83845.14, AC006449.19, AC004019.20, AC009318.11, AC006160.9, AC013429.12, AC011465.4, AP001725.1, AC004253.1, AC006285.11, AC006388.3, AL359382.23, AL031311.1, AC006511.5, AC005088.2, AB023048.1, AC004089.25, AC002470.17, AC023490.5, AC018751.30, AL033529.25, AC011472.7, AC005899.1, AC018663.3, AF001549.1, AL160269.14, AL136137.15, AC007374.6, AC011005.7, L44140.1, AC008753.8, AP000501.1, Z85987.13, AC009570.13, AC005077.5, AL121601.13, AP000556.2, AF030453.1, AC004867.5, AC021016.4, AC007383.4, AL022313.1, Z82215.1, AC020913.6, AE006465.1, AC008616.6, AC018719.4, AC009314.4, AC011464.5, AC024163.2, AC006312.8, U80017.1, AL121890.34, AC018636.4, AL583856.6, AF111167.2, AL136131.15, AF196969.1, AL117336.22, AC005682.2, AC008543.7, AC011450.4, AF037338.1, AP000511.1, AL033528.19, AL137073.13, AC011461.4, AC011487.5, AC006211.1, AC000353.27, Z97832.11, AL121712.27, AL132780.5, AC008745.6, AL096840.25, AC005480.3, AL136979.16, U91326.1, AP002812.3, AC004865.1, AL160471.5, AC008760.6, AC004166.12, AC018638.5, AP003357.2, AC007850.29, AC016995.4, AC073657.5, U78027.1, AC005696.1, AF312032.1, AL356481.16, AC007934.7, AL391280.15, AL139100.9, AC011311.11, AC011484.4, AC004703.1, AC016894.7, AL121992.24, AL121972.17, AC011455.6, AC005288.1, AL109804.41, AC022211.5, AL022320.23, AL049776.3, AC005057.2, AC008806.4, AP001732.1, AC023344.4, AP002852.3, Z99716.4, AL138784.30, AL365364.19, AL031286.1, AC009079.4, AL354707.17, AC020915.6, AP001711.1, AC009244.24, AP000030.1, AP000134.1. HDTLM18 71 836057 1-511 15-525 T62863, AL049843.18. HE2CM39 72 553651 1-552 15-566 AW138760, BG236171, AI928443, AI264363, BF432779, AA581388, BF446513, AW170385, AI366182, AI970247, AA854958, AI354301, AI081061, AI140964, AW243493, AW104079, AI366181, AA732881, AI039682, R46377, AA425694, H11979, AI871576, AI082699, AA428526, AW207325, H72841, AI767870, N35990, AW168999, AI537179, AI678150, AW972093, AI283218, AA405499, Z39960, AI191091, AA626013, AW139286, F03140, AA890408, AI349325, AI871195, AW088879, AI914847, AA192077, AW090285, N95266, AA788656, BE674514, AI634559, AI269823, AA894693, BG109270, AW806761, BG029829, BE965355, AI623941, AI537677, AW169784, AW161156, AI918449, AI538885, AI521005, BF061283, BF853807, AW059828, AI345688, AV743631, BF342261, AI866820, BE138644, AW161579, AI587121, AW302992, BE789764, AI540759, AI348917, AI540674, AI581033, AI349957, AI345005, AW827289, BE048087, BF924855, AL120853, BG164558, BG151388, AW827227, BF812936, BE964614, BG031664, BE047952, BF751347, AW072719, AI648567, AI621341, AI310940, AL041016, AI567582, BE904096, AV750565, BF339322, AW023338, AI698427, AW074869, AA641818, AI859991, BE620444, AV736808, AI874166, AI434741, AV756122, AW268302, BE544111, AI310575, BE878735, BF750879, BG107576, AI307736, AW089275, AI349645, AI919593, AI799674, AI559872, BE910373, AI580674, AW089572, AI568060, AI340533, AI670009, AI921254, AI917963, BE543089, AI890507, BE887488, AI690748, AI340511, AI345608, AW162194, AI473451, AI933992, AW302954, AI800473, AI572717, AL037558, BF753023, BE256001, BE879396, AI288285, AL040241, AI345253, BF680133, AI307494, AI539153, AW151136, AW044029, AI345677, BE138658, AI446373, BE895585, AI340627, AW163834, BE974031, BE963286, AW020095, AV741327, AI494201, BF699668, AI538878, AW263804, BF339594, AI251830, AI813633, AI345745, AI348854, AI345471, AI696611, AI336582, BE886728, BE964683, BE894455, BG114432, AV714085, AV712713, BE965169, N25081, AL037041, AV704350, AI345224, AL119863, BE966699, BG001235, AI868204, BF752999, AA761557, AI267185, AL048323, AW083778, BG249669, BG029086, AA070889, BF904180, AA464646, BG113299, AL048340, AI311892, AW021373, BE621472, AI290153, AL036673, AI335426, AI348777, AW081255, AW772685, AI866770, AI345261, AI702301, BF970449, AW301505, T99953, AI273179, AI805769, BF572734, AL036772, AL036396, AI610357, AA904121, AW058233, BG254745, BF751710, AI436429, BE781369, BF904189, BF726207, BF338002, BF343568, N99092, BE172412, BG166654, AL119791, AA127565, AV755793, AI343059, AA572758, N29277, AW834302, BE890131, BF924856, AW946806, AB063084.1, AL359620.1, AK024538.1, AB050534.1, AL357195.1, AL137665.1, AK026551.1, BC003687.1, AL136844.1, AB048954.1, BC006440.1, AF352728.1, AK026647.1, AL136644.1, AL389939.1, AK026855.1, AB044547.1, AB055368.1, BC009294.1, AL389935.1, AF061943.1, AL512750.1, AK027144.1, AL359622.1, AF028823.2, AL137478.1, AL137547.1, AY034001.1, BC003602.1, AL136768.1, AF090934.1, BC008282.1, AL137463.1, AF026816.2, L19437.2, AK027193.1, AK026746.1, BC000090.1, AF061795.1, AF151685.1, AY026527.1, BC001963.1, BC004530.1, AB049900.1, L30117.1, AK027146.1, AB056809.1, U80742.1, AK026626.1, AB062750.1, BC004244.1, AF205073.1, AL512719.1, BC000051.1, AL136622.1, BC008417.1, AF260566.1, AL050092.1, BC003122.1, AL122110.1, AB063093.1, M64349.1, AK026762.1, AL136893.1, AL049465.1, AK027614.1, BC007499.1, AF111112.1, AK000418.1, BC001236.1, AK026480.1, AL133640.1, AL080154.1, BC001045.1, AF017790.1, BC001056.1, AB049758.1, AF056191.1, BC006133.1, AB019565.1, AB049892.1, AF162270.1, BC009311.1, BC004529.1, AL122050.1, BC002535.1, AK025084.1, AL512733.1, AB056420.1, AK000647.1, AF217982.1, AL583915.1, AL117394.1, M92439.1, AL110218.1, AF271350.1, AL080086.1, BC008196.1, AL512754.1, AL133557.1, S69510.1, AL050116.1, AL122045.1, AL512765.1, AL133113.1, BC008893.1, BC006201.1, S76508.1, AB055361.1, AL137556.1, AK000247.1, AL162008.1, AL136787.1, AK026597.1, AB048975.1, AL137529.1, BC004874.1, AL353940.1, BC006807.1, AF104032.1, X98834.1, BC007053.1, AF051325.1, AK026526.1, AL137574.1, AL137550.1, AB063077.1, AK000310.1, BC002466.1, AL117440.1, AK024546.1, BC004368.1, AJ006417.1, S77771.1, AK026542.1, AK026534.1, AF091084.1, X82434.1, AL122049.1, AL080159.1, AK000432.1, AB050410.1, AK027161.1, BC004362.1, AB060863.1, BC006410.1, AK027182.1, AL389957.1, AB060903.1, AK025015.1, Y14314.1, AL133016.1, AL137558.1, BC001655.1, AL157482.1, AB056768.1, AL080126.1, AL050138.1, AL096751.1, AL136752.1, AL136915.1, BC002733.1, AL389982.1, AL110280.1, U51587.1, AL137476.1, AF230496.1, AK026593.1, AF285167.1, S61953.1, BC008780.1, BC007326.1, AF003737.1, BC004945.1, BC006509.1, AF218031.1, AK025967.1, AK025391.1, AK027121.1, AL512684.1, AK026057.1, AK025410.1, AF218014.1, BC002750.1, AJ299431.1, BC006103.1, AL122106.1, AK000636.1, AF177336.1, AL359583.1, AK026744.1, AL117460.1, AK025632.1, BC007567.1, AL133075.1, BC003548.1, AF090900.1, AF262032.1, AK027142.1, AF125948.1, AF111847.1, BC008078.1, BC002697.1, BC007732.1, AL117435.1, AJ012755.1, AL137479.1, X72889.1, AK027868.1, AK026591.1, AL136799.1, AL080060.1, AL080158.1, AK027102.1, AL512718.1, AK026086.1, AB048964.1, AF217966.1, BC006508.1, AL390154.1, AL512761.1, BC004370.1, AB060873.1, AB060905.1, AB047941.1, BC008280.1, AL133098.1, AK026784.1, AL512746.1, AB047801.1, AF305835.1, AL157431.1, AL133568.1, AL133014.1, AF146568.1, BC006412.1, AK027136.1, AF227198.1, BC007346.1, BC008365.1, AL050277.1, BC006332.1, BC005073.1, AL133093.1, AK000618.1, AL137560.1, BC006832.1, AK026045.1, AF143723.1, BC003650.1. HE6CS65 73 762960 1-1512 15-1526 BG114804, AV718161, BG115294, BG163956, AW362005, AW579708, AA425593, AV732860, AA778426, AW367244, AL537244, AW856936, BF377273, BE675130, BG119784, BF978611, AA194252, AI937228, AW292921, AI222740, BF349929, AW856088, AI348188, AW665835, AA025880, BF333804, AW005582, AI139606, AI126585, AW959277, AI417243, AI339985, AI972128, W52543, AA829354, BF333819, AI078819, AV752850, AW857034, BE789386, AI299395, AW675446, AI083537, AW516855, AA035526, AW005637, AA932845, AI088259, AI492529, BF375157, AI334135, AI682947, AI753237, AI923621, AA425629, BF804458, AI628857, AI635633, AI085676, AI580195, AI138968, BE350523, AA005425, BF333807, AW102884, W52544, AI022376, W39677, AI920867, BF333811, AI240384, N49885, AA227905, AI087384, AI302240, AI933336, AI670129, N98508, AI268859, AA232843, AI221780, AA253379, N71409, AA004925, BF761279, AI066394, BF811217, AI302764, AA311893, AW571609, AI080166, AI299456, AA844294, AI342664, AI147714, AA464423, T60255, BF807121, AA765193, H29427, AA876118, AW265722, AI074827, AA808646, AA193122, H43349, AA233282, AI693779, AI245406, R60024, AA005426, AA995705, AW302271, AA934521, AI061151, AW366962, H38317, T90537, AI445689, W44818, H12893, AI446122, AA253378, H78422, AW378644, AI753445, R44689, N99734, AW102871, AA719170, AA464422, AA974340, H78222, AA934622, AW149309, R68103, AW265649, H40537, AA807276, H43181, AI277059, T34512, AA430350, BE539364, AI076849, AA347001, T81330, BE049268, H26609, AW589372, BG231066, AI092386, R24873, R43362, Z40090, AA334085, AW378680, N31595, H58243, R68147, AA257048, AA004926, H12894, AA886683, BF593823, F02035, AI559907, AW062917, N49990, H43311, AA295950, AI364249, R52133, BF748425, BF804455, AA778257, AW379516, T81506, AI080028, AA347002, BF377711, T83072, AL134712, H26654, BE082628, BF131565, AA227588, BF092102, BE774491, BF092109, AI382725, W63710, BF807108, F01928, BF858654, W31073, AA169731, AW367337, AA936648, AA193460, AW378675, H43212, BE082824, BF858661, AW864790, AA946635, T61637, AA304629, R17644, BE047631, AI867081, T24808, AA293625, R52222, AW890658, AA425423, BF929843, BE888442, C02346, Z99943.1, AK024700.1. HE6FU11 74 827236 1-1986 15-2000 AA992948, AI638341, AW134923, AI038302, H54037, AI581139, AJ007581.1, AK027323.1, AF314058.1, AL021578.4, AB027710.1, AB024964.1. HE6FV29 75 588454 1-1512 15-1526 AA984763, AA406303, AA599164, AA600957, BF922107, AL046225, AI623434, BF760969, AI890702, D29050, AL449223.7, AP000114.1, AP000046.1, AP001717.1, AC006039.2, AL078463.11, AL035460.15, AC060232.5, AL161730.9, AF277315.3, AC010198.8, AC010319.7, AC005099.1, AP003114.1, AC020906.6, AL117377.18, AC004841.2, AL161937.13, AC004951.5, AL161781.12, AL157858.5, AL391260.13, AL158828.14, AP000302.1, AC007193.1, AF123462.1, AC027644.9, AC006254.10, AL035662.65, AL139396.17, AC004084.1, AC015937.7, AF008191.1, AL355916.2, AD001502.1, AF283320.1, AC005082.3, AC005399.19, AC003030.1. HE8BQ49 76 589443 1-1861 15-1875 W35257, AC009225.3, U49973.1, AF036938.1, AL445225.9, AC006142.1, AC006077.1, AC008670.4, Z74739.1, AL023755.5, AC008780.6, AL445212.9, AL356317.8, AL137244.28, AJ271735.1, U70984.1, AF241734.1, AC021506.5, AL391868.15, AL162386.17, AC009312.4. HE8SG96 77 862016 1-2022 15-2036 AV763026, AV763058, AW964231, AI732710, AI732677, AI669589, AW327624, AI061313, AA410788, AA829036, AA502991, AV759632, AW328331, AW973992, BF804385, BF526964, AW069227, AW873261, AA831426, AL039042, AW974932, AV729929, T11828, BE301584, AW576490, T74524, BE138594, AI090377, AW500684, AI821608, AI284543, BG222813, AI244127, H73550, AI755214, AI345695, AI284126, AA535216, AI275982, AI380617, AW237905, AI491765, AU147162, AI754105, AA831638, AI754567, AW026305, BE062478, AI421950, T05118, AI419337, AI755057, AI223626, AI912401, AW516255, AI753672, AI612142, AI056177, R64617, AA683279, AI609972, BF821897, AW576251, BF681619, BF868994, AI361090, AL041706, AW969941, AU159116, AW833047, AI186438, BE062476, AI826761, AW504224, AI254770, BF821009, AA828047, AI049955, AL079734, AW270771, AW468009, AA177011, BE328291, AI251034, BE139139, AI653515, BG223550, BF854308, AK025806.1, AL138707.10, AL138784.30, AC002350.1, AC004166.12, AE006639.1, AC004878.2, AC005071.2, AC004867.5, AP001724.1, AP000688.1, AL034417.14, AL031708.3, AC005098.2, AC007327.1, AC016543.6, AC012596.4, AC004000.1, AC005952.1, AL117341.26, AC005796.1, AC005488.2, AC006014.2, AL031904.1, AJ400877.1, AC022436.5, AP001873.3, AC025594.5, AL161658.21, AC008394.3, AC005246.1, AL158828.14, AC007003.4, AF168787.1, AL031228.1, AL136228.8, AL121834.20, AC090051.8, AL139092.12, AC005529.7, AC005047.3, AC021396.6, AL390738.4, AL391122.9, AC010363.6, AC068799.14, AL035464.20, AC006449.19, AL121753.30, AC004778.1, AP001432.1, AL121901.20, AL391136.9, AP000010.2, AP000151.1, AL022324.1, AC091529.1, AL139415.10, U91320.1, L44140.1, AB038653.1, AL049776.3, AL136123.19, AC008701.5, AL136083.7, AC010412.7, AC022509.21, AL022320.23, AL138756.23, AC005565.1, AL353710.7, AC009961.11, AL121886.22, AL359091.10, AP001068.1, AL023577.1, AL354808.24, AL121653.2, AP000500.1, AC004491.1, AL137141.10, AL078461.38, AL009181.1, AC011450.4, AL138762.20, AF111167.2, AC011460.3, AL137229.4, AC018712.5, AC009477.4, AP001728.1, AC010543.8, AL022318.2, AC005821.1, AC012309.7, AP001714.1, AC009731.6, AB026899.1, AJ011930.1, AL163300.2, AL161781.12, AL354720.14, AL133240.3, AL353802.14, AC074013.5, AC007000.2, AL049795.20, AC079347.6, AC011548.4, AF107045.1, AL031659.9, AP001725.1, AC087590.1, Z68226.1, AL513008.14, AC020904.6, AL033528.19, AC002326.1, AP001469.1, AC004785.1, AL162464.5, Z77249.1, AC069080.12, AP000687.2, AL512590.2, AL133545.10, AC025457.5, AL357712.10, AL121652.2, AL033381.2, AC006023.2, AC009481.4, AP000008.1, AC006312.8, AC023344.4, AC006236.1, AC010358.5, AC004812.1, AC004824.3, AL049565.3, AL133383.10, AL356481.16, AC009996.7, AL391839.9, L47234.1, AL162274.17, AP002982.2, AC004882.2, AC008055.6, AL031727.42, AL117334.29, AC010203.13, AL132780.5, AC007687.16, AC004622.1, Z93023.1, AL118524.25, AL355916.2, AC007404.4, AL079335.29, AC005387.1, AC011449.6, AC005225.2, AC019206.4, AL021977.10, AC011239.5, AL137878.11, AL161899.21, AL158214.33, AL591807.1, AL391221.15, AC006435.7, Z67997.1, AL133507.8, AC005914.1, AC008507.8, AC012476.8, AC008651.7, AC005386.1, Z93244.1, AC010465.7, AL137059.20, AC003969.1, AL117692.5, AL365445.11, AL136039.4, AP001727.1, AC004134.1, AC010598.6, AC006329.5, AL049569.13, AL137061.12, AC010473.5, AC018738.4, AL031428.9, AL109749.22, AC005200.1, AL133260.12, AC004098.1, AC008536.6, AC007277.2, AP000811.4, AL136159.11, AL033543.6, AL158166.12, AC009244.24, AC006057.5, Z81007.1, AC090955.2, AL121992.24, AF274856.2, AC008635.6, AL009031.1, AC004089.25, AC006139.1, AL135787.13, AL133485.3, AC007739.2, AL035587.5, AC011479.6, AL159168.15, AC006480.3, AL139289.6, AP001748.1, AL139396.17, AL161793.9, AC006277.1, AL354760.11, AB014078.1, AC004594.1, AC004976.1, AC012442.7, AL391595.14, AL512347.14, AC011471.6, AC008753.8, Z97985.16, AF283320.1, AP000704.2, AC010320.9, AL135839.15, AC090954.1, U95742.1, AC009248.6, AC018648.5. HE9EA10 78 827796 1-2100 15-2114 AI990816, BG112919, BE503434, AI797355, AW303578, BE502346, AI750156, BE786552, AA514648, AI631128, AU158865, AU148743, AI611129, AU153354, BE540704, AU150538, BF508791, BF223713, N77793, AW103270, AI206873, N62886, AI652672, AW003920, AW515809, AW003207, AI055940, AI039096, AW205084, AI206877, BE175285, AI522151, BE709434, BF436332, AI365206, AI274835, AW798986, AA962334, BF001393, AI220417, AA226874, AA062659, AI696208, AI970440, BF353450. HE9GG20 79 633719 1-662 15-676 AA702942, AA017500, AI590400, AI863074, BF208968, N53688, R50964, H29619, AA053400, M79184, R49619, R07891, R11225, D58339, AA022600, AA704234, H44497, BE567097, BE567104, N54769, AW949478, AV726590, AW958620, AV708961, AV724987, AW953773, AV727381, AW963671, AV702725, AV706223, AV707863, AV703062, AW967188, AV728965, AV706183, AV651920, AV727822, AW959830, AV707786, AV698290, AV702738, AV705445, AV705437, AV702798, AV704847, AW957653, AW954439, AV660258, AV725618, AV726505, AW962133, AV707663, AW964223, AV706279, AW950443, AV697880, AV648364, AW952403, AV726619, AW952751, AV701183, AW956075, AV645936, AW954209, AV709587, AW959858, AV705635, AV692600, AV650315, AV659389, AV727613, AV725033, AV706527, AW964421, AV727787, AV659294, AV725745, AV686060, AW631469, AV660608, AV728148, AV726831, AW950411, AV709314, AV653353, AV727377, AW954697, AV691080, AV702385, AW949802, AV652001, AV707979, AV709580, AV727003, AV707652, AV708786, AV659547, AV727526, AV728546, AV725577, AV728924, AV725617, AW956474, AV704124, AV699089, AV705135, AV701874, AV703501, AV704785, AW952042, AV707401, AV709660, AV709935, AV654035, AV707654, AV704042, AV654282, AV729220, AV697288, AV694836, AV706882, AV697498, AV727314, AV702954, AV727238, AV686420, AV682997, AV696866, AV727126, AV728652, AV655890, AV728997, AV706162, AV686390, AV656256, AV686417, AV698429, AV656240, AV655577, AV692972, AV694871, AV727459, AV695545, AV703762, AV656283, AV656224, AV694674, AV708025, AV684604, AV729378, AV708980, AV692691, AV729131, AV645545, AV706671, AV649758, AV728270, AV709256, AV727103, AV693523, AV706532, AV701496, AV707730, AV727807, AV705811, AV704592, AV703456, AV727032, AV728642, AV701538, AV727029, AV725001, AV702869, AV725380, AV707510, AV727221, AV725956, AV728471, AV726694, AV728985, AV708438, AV702861, AV725134, AV702721, AV728436, AW945153, AW959312, AV703669, AV702794, AW951768, AV654070, AV650430, AV703437, AV702558, AV703620, AV704585, AV651075, AV729077, AV659189, AW960601, AW957068, AW954032, AV651317, AW960779, AW949398, AW952183, AW959806, AV656903, AV697196, AV707656, AV684762, AV656250, AV726091, AV703034, AV707830, AV655280, AW951239, AV659322, AV654908, AV656478, AV698545, AW952885, AV708381, AV660728, AV646808, AV726194, AV703169, AV728715, AV728518, AV728360, AV727912, AV702109, AV696931, AV647789, AV729159, AW966044, U94592.1, Z30183.1. HEAAW94 80 847340 1-910 15-924 AA578368, AA492135, BE707438, AI88012, AA927112, AW970866, AA368674, AW237957, BE560582, BE560540, BE268041, BE513979, BE398109, AI525375, BE270770, AF191611.1, AF043045.1, AF042166.1. HEBCI18 81 831464 1-1107 15-1121 BG163565, AA176798, AW978791, BE551966, AA836133, AW469431, AL134496, AI919296, AA039788, AA039787, AW188317, AI198382, AI302883, AI057154, AW504498, R82599, R87540, AW873029, AW471211, AA912833, BF909811, AI589744, F09143, F10741, R82600, AA984619, T75424, BE328429, R39278, AW517852, BE929822, R88273, R87938, BE929796, AA583730, AW088089, AW169811, BF812441, F13138, F11483, AW008583, BE934536, T94778, AW135926, AW082922, R87937, T63400, T94026, N26157, AI432002, T63545, AI687331, AA983955, AB014522.1. HEBCY54 82 600355 1-1175 15-1189 AL530975, AA747512, AI215061, T15637, Z39819, AA350340, AA866209, R00414, AW074717, F08597, AW953260, Z43761, U97145.1. HEBDQ91 83 840288 1-1559 15-1573 AW964157, AI564075, AA167586, AW204637, R85100, AA824367, Z45398, AA324333, AA332411, AW341163, T81885, BG055317, AA378561, T05032, BE218722, Z41111, T71210, AV705201, AV703158, AW953763, AC008623.4. HEBFR46 84 847064 1-1290 15-1304 BF339246, AW957665, BG258103, AW075995, BF309372, BE868083, AW576203, BF308177, BE881903, BF689190, AI051657, AA311371, BG059809, W56301, AW058408, AA102223, BE301190, AI091799, R05745, D61582, R01123, AA102222, AA375163, BG029189, AW293550, AI752483, AA376452, AW275432, BF812696, AI439525, AW151541, AW084324, AL121039, AW265468, AI702049, AW162314, AW327673, AA577706, BE273825, BF940118, AI270280, AW148821, AW162332, AA807704, BG059139, AA661583, AW238137, AA601674, BG180320, AV742390, BE244308, AW410844, AI433952, AI828721, AA631915, AL079734, BG152746, AW473160, AW021399, AW020094, BE677164, AA728954, AI860423, AI039257, BF679568, AW243817, AI049999, AW148964, AI538404, AI826857, AI753131, AI690379, BE676856, AI003469, AV758870, BF214695, AW502688, AW631267, AI904840, AA603359, AI251696, AI819419, AI090377, AI254508, BE176819, AI554399, AA112864, AI355246, AW151848, AW962971, AI028148, AI308529, BF868826, BF970107, AA507499, AI751698, AL036896, AC006483.3, BC000787.1, AK024787.1, AC010616.5, AK027150.1, AC004659.1, AL078611.1, AK000385.1, AC005519.3, AC009756.9, AC002543.1, AC005052.2, AL354836.13, AC016995.4, AL023879.1, AC003108.1, AL139824.22, AL121675.36, AL358777.12, AC015651.18, AC011444.5, AC004966.2, AC011526.7, AC010319.7, AL121579.4, AL158040.13, AC007421.12, AC005531.1, AL391259.15, AL096701.14, AC002996.1, AC067945.4, AL109923.29, Z97183.1, AL133458.19, AC010271.6, AF279660.2, AL035086.12, AP000280.2, AL445184.11, AC008440.8, AC008848.7, AL139809.16, AC018663.3, AP000039.1, AP000107.1, AF195658.1, AP000557.2, AC004974.1, AC010789.9, AC004552.1, AC004985.2, AL160256.21, AC018633.2, AL121897.32, AC090944.1, AC020983.7, AP001715.1, AC007374.6, AL117382.28, AF207550.1, AC010422.7, AL137852.15, AC008635.6, AL035659.22, AP000463.2, AB017653.1, AL359236.4, AC005358.1, AL035683.9, AL139785.5, AL159168.15, AC000353.27, AC000379.1, L35532.1, AL357972.18, AC011479.6, AL159990.12, AL138849.12, AC008891.7, AP000555.1, AC010530.7, AC008744.6, AC025212.5, AL451162.14, AF167081.1, AC007240.2, AC003007.1, AL512489.11, AC004673.1, AC004752.1, AL138733.15, AL354948.7, AC011740.7, Z85986.1, AC005484.2, AC013355.7, AC016596.5, AL031711.30, U73636.1, AC006064.9, U91327.1, AL031680.20, AC004089.25, AL132640.4, AL109935.39, AC010326.6, AC007676.19, AL133229.40, AL136228.8, AC018797.4, AL033519.42, AL096791.12, AL391139.19, AC002312.1, Z97054.1, Z83840.7, AC004821.3, AC002060.3, AL139184.8, AC005280.3, AF107885.2, AB032485.1, AP000256.1, AF312032.1, AL035705.22, AC012379.7, AC020904.6, AC008521.5, AL356214.20, AF224669.1, AP000691.1, AC018673.4, U07561.1, AC008392.6, AC004263.1, AP002906.2, AL031058.1, AL355480.22, AC006530.4, AC009362.8, AF258545.2, AL049759.10, AL035249.6, AL008582.11, AJ009616.3, AL050404.3, AL122020.5, AP000098.1, AL133163.2, AC025166.7, AC087311.22, AL513366.11, AL353678.11, Z97632.1, AC005041.2, AL121586.31, AC006449.19, AC010412.7, AL355336.15, AL022316.2, AL353748.13, AC010526.7, AC005911.6, AC016025.12, AC084864.2, AC004066.1, AP001748.1, AC026120.33, AL050307.13, AP000361.1, AL157372.18, AL353710.7, AL049780.4, AC011895.4, AC005695.1, AL161937.13, AL354928.9, AC008738.6, AC008372.6, AP000503.1, AC002404.1, AC008482.5, AL121967.11, AC010378.6, AL449209.2, AC026672.44, AL356805.5, AL031662.26, AL449143.18, AL034369.1, AF134726.1, AL049843.18, AC008623.4, AC072061.8, Z98948.1, AC004662.1, U62317.2, AC012476.8, AC008397.7, Z98752.16, AL161670.4, AC007957.36, AC009399.5, AC008755.6, AF317635.1, AC009812.17, AC002546.1, AC003043.1, AC022211.5, AC007746.3, AL050335.32, AC005015.2, AC022405.5, AC004476.1, AL109804.41, AF001549.1, AC016602.6, AL109799.6, AC008044.4, AC004851.2, AL049795.20, AL162505.20, Z83851.17, AL359541.11, AL031282.1, AC009470.4, AL034422.24, AL133332.12, AC005365.1, AL157789.6, Z98051.6, AC006151.3, AC024561.4, AC009086.5, AC005570.1, AC010679.6, AC009469.4, AC008857.5, AC007845.12, AC005091.1, AL132713.11, L78810.1. HEBGE07 85 798096 1-1853 15-1867 AI016066, AC010170.3, AC006515.7, AC008641.6, AC019086.7, AC016587.7, AL078581.11, AC037433.6, AL121975.9, AC022267.8, AC009225.3, AC091493.1, AC006257.1, AL160411.25, AL033397.7, AL122023.3, AP001671.1, AL121983.13, AL024506.1, AL135785.10, AC079383.17, AC024085.5, AC020552.4, AC087069.2, AC008115.3, AL162571.9, AC078841.4, AC008543.7, AC083876.2, AC005071.2, AC019041.8. HEBGE23 86 836129 1-405 15-419 AI916699, AI125755, AI569944, AI199740, AW339714, AW629416, AI983107, AW168252, AI709247, AW129523, AA932741, AA609646, BG056312, AI760369, AI936750, AI521565, AI440301, AW055303, AI479624, AA010077, AA632342, AI147442, F22819, W18188, AW081397, BE222356, W60994, AI689599, AI431516, AI885069, BF510349, AW503732, AA889231, AW591734, BF476512, AA878702, R20641, AA400446, AI971324, AA868098, AI797356, AI810231, AI468652, AI492286, AA235851, N95625, AA954572, AW665137, BE856112, R73152, BF003059, AW002465, AA400572, AW472891, AW964023, BF437333, AI202466, H02677, H16169, AI439020, AI435394, AA522469, AI857711, AA377384, AW029380, H13164, BF475393, AI823448, H04518, AA613532, Z25127, AW771867, AI270235, H03230, AW953787, AA601925, AA165368, AL045450, AW241567, H04020, AI917425, AI336145, AA364034, N88039, N66226, AA419377, AI650474, AW237069, W94707, AW316806, C01430, AK025939.1, AC006486.1, AB002304.1, AC004987.2, AC004842.2, AL035696.14, AC005627.2, AC018638.5, AC073135.3, AL137028.9, AF109718.1, AC010507.5, AL133216.10, AC004916.2, AC012441.3, AC006328.5, AC012005.4, AF270605.1. HEGAU15 87 834379 1-1111 15-1125 W92008, W92009, AC009404.5. HFCEI04 88 692438 1-873 15-887 HFEAY59 89 658685 1-1139 15-1153 AA339768, AI150703, BE386477, AC005919.1. HFEBO17 90 852218 1-976 15-990 AW473576, AI089774, AW451782, AW295271, AA749033, BE440149, AI949946, AI469900, N68539, AW172942, AI872021, AW243195, BE858872, AI337875, AI376876, BE327191, BF939700, AI363093, AI471556, AI767259, BF114982, AI683261, AW028130, AW976177, BE349166, AA974484, AW027661, AI683115, AW614790, AI421188, AI281604, AW239182, AI750006, AW235809, AI493809, AA455090, BF878349, W37813, AV650898, F09284, AW193169, AA703436, AV649714, AA526238, Z41088, AI700797, AW268135, T92246, AV662283, AI916032, T17498, F02060, AV650183, BF768675, F04236, AA935093, BE884109, AV649952, AA937505, AV649940, W37230, AA585284, AV649786, AV651140, AW976261, AW365708, AL137741.1, AK000272.1, BC001249.1, BC000937.2, AL162084.1, AL157494.1, AK027465.1. HFIJA68 91 847074 1-1143 15-1157 AA032221, BE881257, BF573995, BE875216, AI686139, AL048969, BF826830, BE061906, AU157011, N49425, BE775020, AV763498, AA974503, AV710762, BF525393, AV696428, BE972379, BF667616, AI354847, BF038189, AV691908, AW405593, AV684596, BF916850, BG260565, AC004969.1, AC005061.2, AC005053.1, AL109827.8, AF186249.1, AC009144.5, AP003357.2, AC006277.1, AC006435.7, AC023105.7, AL050335.32, AF243527.1, AC005323.1, AL022165.1, AC024561.4, AC004848.1, AL353807.18, AL445584.16, AP000030.1, AC018638.5, AP000505.1, AC012476.8, AL035458.35, Z85987.13, AC009060.7, AP000152.1, AC073657.5, AP000044.1, AP000112.1, AC006571.12, AC026888.6, AL022163.1, AC008569.6, Z98742.5, AL118501.22, AP001412.2, AC007845.12, Z85986.1, AP001711.1, AL035072.16, AL355392.7, AF045555.1, AL049776.3, Y14768.1, Z97985.16, AC011443.6, AL445490.6, AL117336.22, AP001716.1, AC020916.7, AC090426.1, AC008753.8, AL359091.10, D88270.2, AL583856.6, AL096791.12, AC007637.9, Z93017.6, AL050318.13, AC010150.3, AL365505.15, AC005049.2, AP000692.1, AC005250.1, AC007546.5, AC087071.2, AC006285.11, AL033529.25, AL121594.6, AL160269.14, AL136300.22, AL356481.16, AL158830.17, AC019205.4, AC007216.2, AL133448.4, AP000501.1, AC018828.3, AP001760.1, AL158198.14, AC008892.5, AC022415.5, AL109797.18, AC011497.6, AL132780.5, AC005480.3, AC004099.1, AL133249.1, AL121655.1, AC005375.4, AC009961.11, AC005522.2, AC011895.4, AC016025.12, AC012170.6, AL356652.19, AL117381.32, AL158823.11, AL138724.12, AC005914.1, AL163201.2, AL078461.38, AC034193.4, AC006057.5, AC021999.4, AL139415.10, AC004967.3, AL450339.5, AF129756.1, AC005231.2, AC002072.1, AC002070.1, AC005387.1, AL121658.2, U95742.1, AL022721.1, AC011484.4, AC010618.7, AC016830.5, AL161670.4, AC006130.1, AL138836.15, AL137792.11, AC005778.1, AL121905.23, AL049869.6, AC005081.3, AL359236.4, AC020750.3, U95740.1, AL137012.6, AC002350.1, AL121992.24, AL139809.16, AC005519.3, AL121601.13, AF196969.1, AC004990.1, AF168787.1, AL136981.22, Z98946.15, AL133373.5, AC005500.2, AF254983.2, AL049539.21, AL355094.3, AC010463.6, AL121972.17, AL354707.17, AC010530.7, AL022323.7, Z99716.4, AC007193.1, AL121926.24, AC073138.3, AC073073.2, AC005077.5, AL360169.17, AC009244.24, AP001728.1, AC005332.1, AL157823.9, AC020931.5, AC018758.2, AC005052.2, AC007387.3, AL135927.14, AC007227.3, AL359644.10, AC072052.6, AC005251.1, AC018636.4, D86992.1, AC006449.19, AL021397.1, AP001753.1, AC005291.1, AL031846.2, AL133517.11, AL359092.14, AC007242.3, AB038653.1, AC018711.4, AC022148.5, AL136137.15, AC025168.7, AC011005.7, AC004867.5, AL136126.34, AC025588.1, AC009087.4, AP001714.1, AC018506.4, AC034240.4, AC073866.16, AC007991.7, AC011465.4, AL121886.22, AC007731.14, AL356915.19, AL109654.22, AC008610.6, AJ246003.1, AF134726.1, AC008543.7, AC004883.2, AC005736.1, AL391114.12, AC069255.18, AL135839.15, AC006345.4, AL391749.4, AC007488.15, AL137918.4, AP001731.1, AL157373.23, AC000360.35, AC004873.3, AP002428.3, AC005399.19, AC005280.3, AC005200.1, AL391137.11, AL080242.11, AC007263.4, AL110502.1, AC026464.6, AL031311.1, AC020983.7, AL136980.5, AC026448.5, AC004643.1, AC024166.3, AL136295.3, AL139317.5, AC002091.1, AC073136.6, AC008403.6, AP000134.1, AP000212.1, AC004686.1. HFKES05 92 827572 1-1871 15-1885 AL523262, AL529538, BE899393, AW084916, BE747028, BF311012, BE728739, BE312851, AL040564, BE742382, BE735998, AI381488, AI146820, AW161993, BF529932, BE383932, BE259400, AV710840, BE382374, BE744761, AL043582, AW439423, AL043581, BE646448, BG171573, BE677335, BE677477, AI554451, AA131317, AW088167, BF314148, BE261821, BG166503, BE279879, AW168887, BE646180, BF316303, BE046496, BF197687, AA744952, BE745721, AI218269, BE312818, BF314164, BF594180, BF314798, BF593719, AI151026, AA194202, AI418964, AI453314, AI873815, AW130388, BF913893, AA195161, AI269934, AA719396, AA625370, BE312619, BE252921, BE207433, AA492412, AI042024, AW250536, BF573185, BF037936, BG179218, BE302543, AA194044, AI147243, AW340657, AA947438, AI091020, AW117635, BF570164, AI445860, AL045225, AA115998, AI021898, AW732559, AI421387, AU152077, AA968905, AW662299, AA837991, AA131418, BF812798, AA194939, AL043070, AI948633, AW249876, AA195538, AA506433, T16224, AI589527, AA936491, AW016162, AA883810, AW118179, R54823, AV690033, AI560986, AV688867, AA459190, AA354156, C18845, AA378263, AA862775, H61307, AW806534, R45155, AW263382, AI277162, BG254511, W79694, AA458974, T31333, H39688, T34870, AA456441, AA301052, R40792, AL523263, C18401, R87505, AA063352, BE140370, R13315, D20272, BF568555, BE242030, BF033566, AI364386, BF940389, AA301053, AW419282, AW274389, H62348, BE938508, BE832988, BF569370, R87587, T65226, AI940182, BF844052, BE243197, AW886929, D61554, AI254353, T65265, AU124203, BE207881, AA194949, AA569639, AV762557, AV762552, AA862769, H18657, D83782.1, AK027402.1. HFKFX64 93 566835 1-765 15-779 AI202664, AB051500.1. HFPCZ55 94 840840 1-2721 15-2735 AV714494, BG257295, AU137860, AA455877, AA999864, AW880615, N98831, BE048764, AW954901, BE348449, N66571, AL045243, AI420623, AI817146, AW271213, AU157344, W44682, BF955185, BE223107, AI355752, AA455880, R54821, BF589210, AI924033, AI887849, N63487, AW601474, AI923020, N63481, AW903942, AA975919, AI306145, BE767078, AA256290, R72348, N94787, BF948057, AI919421, AW880496, AW005707, AI584169, AA669696, BF754698, H10056, AI250173, AA318076, AI440227, BF001047, AW244040, H10110, N94780, N44348, AA312915, R55120, BF944396, AI358104, AW883910, AI886676, AI418315, BE838574, AI570333, BF588691, AW880645, BF909132, BF932028, BG153080, AV758808, AI345677, AI866820, AI345608, AI340533, AI348995, BG029829, AW268261, AI623941, AW020592, AI348847, AI310582, AI310606, AI345527, AI340511, BE393551, AI307569, AI524654, AL119791, AW079334, AA575874, AI336503, AW238688, BF680133, AI249877, AI344819, AI336633, AI345397, AI345567, AL515047, AI345261, AI345253, AI348870, AI345471, BE011880, BF672397, AL037582, AL037602, AA502794, AW151136, AI310940, AW265004, BF885082, BE965121, BE964700, BF924884, BF904194, BE907440, AW268072, AW191844, AI379711, AI343091, N63128, AI446373, AI573026, AI636619, AI582434, AI366992, AA070889, AW152182, AI312210, AI805688, AI334895, AI801325, AA493647, AI336512, AI473451, AI537677, AA761557, AI613343, AW162189, AA259207, AW303089, AW411043, AI859991, BE543089, AI784214, AI539771, AI929108, AI583032, AW089275, AI801556, BF816042, AK002039.1, AL117524.1, AC073125.5, BC003056.1, AC006112.2, AL360267.10, AC026307.16, Z83840.7, BC008040.1, AL121949.13, AK026793.1, AL512733.1, AC020904.6, AF218031.1, AL049423.1, AL136766.1, BC006181.1, AC004383.1, BC000316.1, AY007109.1, AF132730.1, AL359894.9, AK000655.1, BC006180.1, AC026756.15, AF245044.1, AL161804.4, AK026927.1, BC003122.1, AL512454.6, AC004057.1, AF044221.1, AC002538.1, AC009087.4, AL133069.1, BC004937.1, BC002485.1, AB055303.1, AB060887.1, AC007383.4, AF217973.1, BC002849.1, AF162270.1, BC004908.1, AC005815.1, AL049557.19, AK027162.1, AF285836.1, AF271350.1, BC006472.1, AC010137.3, AK026542.1, BC007255.1, AL117416.1, AK000568.1, AC083867.4, AK026649.1, BC006832.1, AK025435.1, BC003548.1, AF061795.1, AF151685.1, AL137479.1, AL137267.1, BC000007.1, AF111112.1, Y13350.1, AC010723.3, AC010530.7, AK026528.1, AK027095.1, AL122106.1, AK027164.1, BC001977.1, X72889.1, BC002733.1, AK026462.1, AK000137.1, AL162713.19, Z82206.1, BC008365.1, BC004362.1, AL157694.7, AL110158.1, BC008282.1, U77594.1, BC001767.1, BC008364.1, BC008718.1, AC009233.3, X83544.1, AB050534.1, AC019176.4, AK025407.1, AK000421.1, AL356747.18, AC004837.1, BC005678.1, AP001666.1, AL135796.6. HFTAS49 95 847386 1-504 15-518 AI086076, BF432976, BF110160, AI493530, AA573873, AA594551, BF967837, AA086458, AA479474, AA505932, AI652271, AI654799, AA838460, AA150300, BE813563, AA148791, BF939030, AI126256, AA030012, W05069, BF447699, R34884, BG055342, AA446652, AA643067, AW062717, AW062693, N51389, AI032793, AA629918, BF945961, AI289025, AA447455, AI435022, AA479820, AA781029, BF437593, AA256802, AI341331, BE817212, AW954578, H62050, AI184633, BE502174, R36678, AF034174, AA215717, AA284655, AW665402, AW675233, BE674245, BC007727.1, AF062529.1, AF062530.1, Z98036.1. HFVHW43 96 570948 1-1219 15-1233 AI761677, AL047645, BE243506, AA169245, BE246405, AA536127, BE064798, AI364568, AW575409, AW085690, AI298660, AW844145, AA492266, Z23150, AI281401, AA247731, AI078409, AL132795.12, AC009274.9, AL133324.13, AC034245.4, AL158207.15, AC016831.1, AC011491.5, Z82242.1, AC008391.5, AF110184.1, AC004659.1, AL161665.5, AP000689.1, AL158830.17, AL035685.21, AC005000.2, AL353692.14, AL451162.14, AL133551.13, AC005057.2, AL133382.8, AL353614.9, AP000338.2, AC009247.12, AC005327.1, AP000216.1, AC008753.8, AL357519.19, AL157372.18, AL162578.13, AC005722.1, AP000499.1, AC005208.1, AC016697.8, AC005913.2, AL121658.2, AC008745.6, AL137067.7, AC006111.3, AF235097.1, AL050341.18, AC004216.1, AC011455.6, AC079754.4, AC053467.1, AC008755.6, AC005412.6, AC022211.5, AC011461.4, AL121655.1, AL121653.2, AL079342.17, AC009470.4, AC016637.6, AL133347.28, AC004826.3, AB026898.1, AP003357.2, AL391834.8, AC021999.4, AP000744.4, AC022007.3, AC005844.7, AC020754.4, AF111168.2, AC005355.1, AC007773.1, AL139390.15, AC007383.4, AC005104.1, AK022308.1, AC020916.7, AC013429.12, AC012170.6, AL354674.5, AC004150.8, AC004129.1, AC022002.4, AC005839.1, AL136992.22, Z97054.1, AF038458.1, AL158198.14, AL050335.32, AL121920.21, U52111.2, AL136979.16, AC020744.4, AL450346.4, AC004262.1, AL137139.9, AK022406.1, AP001063.1, AL133312.3, AC020550.4, AC002115.1, AP003475.2, AP001760.1, AL499628.1, AL035249.6, AL354928.9, Z99916.1. HGBER72 97 826710 1-1302 15-1316 AI827764, AW963463, AV728410, AW964231, AV705122, AW956640, AW963895, AW956641, BF918640, AV702172, AI732151, AW958318, AW021917, AV759632, AW974932, AV702109, AV704541, AV704467, AV705086, AI962030, AV725237, AV711430, AW500029, AW956077, BF760919, AV762633, AV703573, BF804385, AW962006, AW970877, AW302909, AA905613, AV728369, AV763026, AV763058, AV702760, AI188390, AV729337, AA644090, AW969743, AI358384, AV729272, AV702343, BF750422, AW962942, AV726091, AW963497, AV703597, AW973992, AW960468, AV709273, AI305766, AV762454, AW966064, BF911056, BG236628, AW963542, BE063437, BF916934, BF347791, AW410354, AI017251, T05834, AV762982, AV711465, AW955841, AI279417, BE150580, AV762033, AA584489, AA904275, AL040054, AV757607, BE019467, AV758903, AV728425, AV703063, BF347740, AI963720, AW816516, BE294700, AL042373, BE395467, AW963489, BE178609, AA720732, AV712092, AW514662, AW069769, AW731867, AA574442, AV759557, BG029528, AV764259, AF246229, AC007731.14, AC005500.2, AC004033.3, AP001725.1, Z98941.1, AC005391.1, AL353653.19, U78027.1, AL034405.16, AC002301.1, AC004477.1, AL121897.32, AL133396.2, AC018638.5, Z83844.5, AC020916.7, AL035587.5, AL391241.21, AL096791.12, AL096865.28, AC002542.1, AL035422.12, AL117694.5, AC008543.7, AC005037.2, AC005841.3, AC005756.1, AL133551.13, AL109758.2, AL021155.1, AC006241.1, AC011464.5, AC008754.8, AL049643.12, AL138740.9, AC007536.9, AC020947.6, AC006211.1, AC079602.15, AC011495.6, AL136084.11, AL031685.18, AC004771.1, AL031432.1, AC008750.7, AC005701.1, AC008044.4, AC004840.3, AL139022.4, AL135927.14, AC007227.3, AC005821.1, AC004841.2, AC005399.19, AC007204.1, AB016897.1, AC083872.2, U02532.1, AE006462.1, AC011452.6, AL445685.17, AC006958.1, AC061709.25, AF196779.1, AJ009611.6, AP000692.1, AC005484.2, AC006345.4, AC005921.3, AL391262.3, AL512430.14, AC002563.1, AC004815.2, AC006055.1, AC006130.1, AC009756.9, AL139188.14, Z85987.13, L11910.1, Z81364.1, AL023807.6, AC009086.5, AC068799.14, AC004882.2, AK000254.1, AC013717.8, Z98257.1, AC008372.6, AL031295.1, AC000086.1, AC006543.7, AC008622.5, AL157369.7, AL136418.4, AL139054.1, AC008736.6, AC002425.1, AL157938.22, AC002565.1, AC005833.1, AC004824.3, AC010206.8, AC010422.7, AC002133.1, AL132653.22, AL109743.4, AP001693.1, AC008395.6, AL449209.2, U73024.1, AC011514.3, AL133545.10, AB055358.1, AC009488.5, AC010768.9, AC005971.5, AC006451.5, AC005666.1, AP000208.1, AP000130.1, AC006052.5, AL158141.14, AP000665.5, AF010238.1, AC011529.3, AL009178.4, AC006511.5, AL122001.32, AC004150.8, AL021918.1, AL133174.15, AL158207.15, AC007201.1, AC008745.6, AC068533.7, AC009087.4, AP003352.2, AL033383.26, AC002472.6, AC006111.3, AL034417.14, Z82182.2, AC006312.8, AP000842.4, AC007546.5, AL442167.1, AC025447.4, AC009220.10, AL121928.13, AL049868.20, AC006544.19, AL022322.1, AF348209.1, AC010328.4, AC004821.3, AC018926.10, AL034549.19, AC006061.1, AL163285.2, AL049843.18, AC019171.4, AL096840.25, AL359846.11, AC008551.5, AP000251.1, AC007136.1, AF031078.1, AP003475.2, AL354864.16, AC010465.7, AC005330.2, AC010368.4, AL121992.24, AF045555.1, AL450339.5, AL117352.12, AC008101.15, AL445263.6, AF168787.1, AC004913.2, AC004816.1, AC011453.4, U91318.1, AL449305.4, AL109627.18, AL022327.17, AC004765.2, AL049872.3, AC008906.5, AL137918.4, AC025457.5, AC025280.4, AF030876.1, AC012594.7, AC034193.4, AC005546.1, AC005306.2, AL022329.9, AC006483.3, AC007388.3, AP001714.1, AC008397.7, AF001550.1, AC018828.3, AC003007.1, AP000111.1, AL133347.28, AC010358.5, AC009060.7, AF038458.1, AL035696.14, AL031587.3, AL359091.10, AC022382.3, AC005180.2, AL137792.11, AL109801.13, AL121914.31, AF053356.1, AC022211.5, AC009570.13, AL022476.2, AC003046.3, AC004686.1, AP002906.2, AC019205.4, AC006388.3, AC025593.5, AC002115.1, AC011479.6, AC004752.1, AC008269.4, AC004836.2, AC005215.1, AL136304.10, AC003108.1, AL137145.13, Z95331.2, AC011737.10, AL162455.14, AL133246.2, AL034380.26, AP001711.1, AC008403.6, AC002044.1, AC026172.3, AC008079.23. HGBHP91 98 693011 1-1040 15-1054 AA825851, AA736485, AA805014, AI792627, AI862231, AW086361, AI348722, BE139397, AI254439, AI349662, AI053450, AI053903, AW102980, AC005017.1, AL591770.1, AC005484.2, AC018523.9, AL137190.5, AC016691.10, AL354751.7, AL513366.11, AC009137.6, AC083871.2, AC024166.3, Z77249.1, AL161670.4, AC007934.7, AL137139.9, AB026898.1, AL353613.10, AC018494.6, AL110502.1, AC026770.6, AL031053.1, AC073366.3, AC005014.1, AL138499.4, AL158828.14, AP002982.2, AL133396.2, AC007619.22, AC007327.1, AL022723.4, AC004832.3, AC004491.1, AC005189.1, AC009483.3, AC003950.1, AC009961.11, AL031681.16, AC004813.2. HGLBG15 99 701990 1-764 15-778 AI377951, AA478899, AL521476, AI970420, BF571396, BF690972, AA478780, AI522149, BF571271, AA758425, AW956237, BF692249, AI954716, AW197154, BF576614, AI631753, AI829079, AI765476, H99846, AW274419, AI371713, AI951909, AW769338, BF516230, H19109, AI925973, AI932682, AI138219, AI301748, AI956119, AI755080, AI378559, AI080154, H05933, BF000829, AA031313, AW090099, AA736498, AA852791, AA852790, AA928061, AI699043, AI087918, AI468315, R56048, AI469137, AA248855, AW517996, BF541232, BF838384, Z38380, BF838382, AI760228, R55989, AL136597.1, AC005082.3. HHEAK45 100 765278 1-2000 15-2014 BG170168, BG119757, AU137041, BF307487, AI884713, AW583171, BF684161, BF434422, AI761426, AW961739, BE388217, AI816016, AI361955, AA808964, AU156996, AI869337, AA131094, AW291287, AW043617, AA535378, AW614114, AI249699, AI361947, AI218746, AI827821, AI139529, AI221685, AW961740, AI123285, W72783, AI469925, AL049086, AI076164, AA448078, N79760, AA927285, AI130718, AW103188, AA902207, W74291, AW015957, AW473667, AA447579, AI770126, AA886775, AI001738, AA884899, AI948509, BE467312, AW882943, AI765248, D12320, N72712, AA758092, BE295299, W79163, AI624834, N39042, BF822970, H23141, AA347762, W07208, BE940629, AA889154, AI081857, AI205834, AI377270, AA115546, AI220570, W02262, R42088, AW072212, N93000, R00155, W72784, AA677121, R00154, AI160329, AW450558, AA905549, F04905, H53287, AW262887, AA130970, BE856483, AI632990, W21211, AA115083, AA347763, N48234, AA907343, AI247907, AA665725, H78076, AW366883, AK001963.1, AL035690.10, AC010388.5, AL136839.1, AF086405.1, AC007533.2, AC010209.13, AL133341.12, AC023512.28, AC008379.6, AL033529.25, AL110120.11, AL133271.22, AC006022.1, AL138721.16, AC004694.1, AC005899.1, AL117694.5, AC004129.1, AL359236.4, AL121906.18, AC002465.1, AL133510.13, AL132986.4, AC004263.1, AL512782.6, AL035423.4, AB020867.1, AC008088.8, AC005821.1, AC008012.8, AL138878.10, AC087730.2, AC022509.21, AL391684.6, AL024474.1, AC012499.7, AL356969.12. HHEOW19 101 886174 1-1575 15-1589 AL526527, BG113611, BF978449, BG112152, BG119645, AW956161, BG180022, AW592434, BF434127, AI688154, AA890706, BE266768, BE700345, AI192484, AA908255, AA516363, AA446942, AW172490, AA923183, AI499002, AI766675, AI203601, AA894580, AI144379, BF346299, BF969646, AU118533, BE887334, AV760144, BE874811, AA865339, W72592, AW005448, AU143717, AU142574, AA906273, AI021941, AU128074, AW663560, AU131132, AI304388, AA669930, AI304344, AI346611, AU125747, AI311556, AA703026, AI266188, AL516896, AI025716, AA907108, BE390622, AI870412, AI870389, BE785805, AI288868, AA733097, BE789031, BF027056, BF035717, BE870307, BE389154, AL538540, N21316, BE780661, AA075002, AU129647, BG178120, AA774581, BE786810, BG165094, AA075113, AA443366, H70758, BE387196, AI525737, BF346268, AI264657, AA676415, W80864, AA644550, AI023409, AA772235, W67811, AW501988, AI807013, AA299952, AW474224, AI269880, AW629279, BG177563, BF800060, W67866, BF034810, BE547050, BG028159, BE083939, N80176, AI051331, AW592042, BE247222, AI201765, AA860195, AA081004, BE244890, AA019463, N34142, W88877, AI193593, N67021, AI192316, AW795216, N26033, BE084138, BE002622, AI084602, BE774587, BE832659, W76106, AW140058, N42641, BE832664, AA058752, AW994714, AW994775, AI768257, AA018536, AA888922, AW085016, W42800, BE093798, AA706242, AW994696, BE813681, AA384060, AI860208, N46027, AA081147, R96612, AA887957, BE708347, AW993971, AW192384, N41872, BF794279, AU120547, AA370582, BE832568, AW591801, AW236343, AW157602, N40396, AW294314, AW272410, AA723436, W35238, N31251, AA886238, BF817120, BF818982, AA373471, AW131477, H95094, AA808734, AI871211, AL038165, H79809, AI904418, AA534807, AI799628, AA299951, BF361806, AA001163, AA608755, BE798428, BE084059, AA988507, AI761279, AA564284, BE002993, AI949117, BF817107, AV756014, AW384875, AA393462, AW514936, AA454946, AA922856, AW408230, N30627, BE779312, W81429, BF448458, AA876205, H58732, AA831555, BG166267, BF695720, AI743703, N56626, N66943, AA017731, AV684502, AA724567, W24284, BG164949, AW957013, AA724553, H03450, BF056116, AL522121, H03534, W80538, AA193154, N30204, N44250, AA485314, AA485471, AI630146, AA806310, AA400785, AL043900, BE160214, AI338385, N36376, BG014060, AU133112, AW273251, AI218055, BE868284, AA923109, N36810, AA814225, N84302, AA017732, AA313506, AI906913, AI341766, N76206, AI298554, W03500, AW002024, W86743, AA746052, BF365269, W81430, AI351319, AC006001.2, AF098276.1, AC027644.9, AJ250042.1, BC000882.1, AF098275.1, AP002827.3, D13641.1, AC004074.1, AF098274.1, AC008267.6, AC005077.5, AK001702.1, AF126961.1, AF126960.1, AF126962.1, AC005231.2, AF126958.1, AK026600.1, AB060825.1, AC006285.11, AK024538.1, AL122050.1, AC016025.12, BC002733.1, AL137538.1, AB056809.1, AK026927.1, AL136787.1, AK026480.1, AL049466.1, AL110196.1, AB063071.1, AL162006.1, AL122093.1, AL050277.1, AL110221.1, AL110225.1, AK026629.1, AB055361.1, AK026506.1, AK026542.1, BC008387.1, AF091084.1, AK026583.1, AL049430.1, BC001967.1, AB048954.1, BC008070.1, AL133080.1, AL050146.1, AL050393.1, AL389935.1, AF090943.1, AL049452.1, AK025084.1, AK025092.1, AL122100.1, AF090886.1, AL136789.1, AL136586.1, S78214.1, AL136882.1, AL137478.1, AB048953.1, AK026959.1, AL136844.1, AB063046.1, AK026784.1, AL133072.1, U42766.1, BC003687.1, AB019565.1, AK026741.1, AF017790.1, AL133557.1, AL050108.1, BC007021.1, S61953.1, AK027113.1, Y16645.1, AL049283.1, AB047615.1, AK000137.1, AB055366.1, AK025484.1, AL136892.1, AK000486.1, AL133560.1, AB051158.1, AK026744.1, AK024992.1, AK026086.1, AL117583.1, AB060908.1, AK025491.1, AL050116.1, AF125948.1, AF097996.1, AB060916.1, BC001045.1, AL512689.1, BC007199.1, AF217982.1, AL050024.1, AL137459.1, AK000083.1, AK027204.1, AL359615.1, AL442082.1, BC006807.1, AL133565.1, AL049464.1, BC005858.1, AK000618.1, AB055315.1, AB056420.1, AL136893.1, AL133075.1, AL117457.1, AL133016.1, AL157482.1, AL512719.1, AL512718.1, AF090900.1, AL389939.1, AB049892.1, AF218014.1, AK026045.1, AK026647.1, AL049314.1, AL390167.1, AJ242859.1, AL136747.1, AK025015.1, AL096744.1, AK000323.1, AL442072.1, AB060914.1, AL117394.1, AL136749.1, BC008488.1, AL137283.1, AK000445.1, AB060893.1, AL136780.1, AK000212.1, AB062938.1, AB060852.1, BC008417.1, AL137550.1, AL133606.1, S76508.1, AK026592.1, AK027868.1, BC008365.1, AL136799.1, AB060826.1, AF078844.1, AL136928.1, AK024588.1, AB063070.1, AK026855.1, BC008899.1, AK026522.1, AB060863.1, AL117460.1, AK025239.1, AB052200.1, AK027142.1, AB047904.1, AF260566.1, AL136845.1, AF106862.1, AL080124.1, X82434.1, AL137557.1, AL133640.1, AL512754.1, AL133081.1, AL353957.1, AL117585.1, AL359601.1, AB055368.1, AL136768.1, AF090903.1, AL050149.1, AF262032.1, AK000206.1, AF111847.1, AL157431.1, BC004556.1, AL359620.1, BC006195.1, AL122123.1, AB060912.1, AF090934.1, BC001418.2, AL512746.1, AK026526.1, AF125949.1, AL359618.1, AL137521.1, BC007326.1, AK027096.1, Y10936.1, U58996.2, AB052191.1, AL137648.1, BC004195.1, AK027213.1, BC007674.1, AK027200.1, AF219137.1, Z37987.1, AK026452.1, AK025772.1, AL512765.1, AL136864.1, AB062978.1, AK024524.1, BC003683.1, AB048964.1, AL136615.1, AK025339.1, AF225424.1, AL512733.1, AL080137.1, AL133113.1, AF061943.1, AL122110.1, AL137429.1, AK026057.1, AK026353.1, AK027082.1, AK026613.1, AB047801.1, AB055303.1, AB060887.1, AK026534.1, AL080060.1, AL110222.1, AL162083.1, AK027114.1, AK025410.1, Y14314.1, AF146568.1, AF090896.1, AL117435.1, BC008983.1. HHFEB79 102 1300768 1-3154 15-3168 AU132655, AU132630, AU119199, AU125675, AU119524, AU121324, AV734096, BF346183, BG258593, AW959138, BF668482, AA206986, BF878396, AW582926, AI479712, AU145602, N36814, AW377557, AI769201, AA479691, AI540203, AL035761, AI912290, AU145838, AW753484, AA099572, AW959334, AW402467, AA479812, AU149286, AI422022, AA776463, AA535858, AU154148, AI016198, BF361274, AI560927, AU147170, AI343877, AI364588, BF061403, BF431914, AA847209, AA770509, BF811269, N69321, BE244691, AI201680, AW512169, AA101976, AW571674, AI318104, BF850279, BF885693, AA150971, AW629417, BF436279, R59541, AW129185, AW117254, BF850275, AA905745, H11046, BF877950, R60441, AV660512, AA361712, BF849362, BF850278, T52687, BE836494, AW583948, R59542, BF701717, AI674499, R50972, H71487, BF822478, H00394, H11134, AI370388, T34497, AA345282, N46032, BE702756, AW504892, AA533890, AA550718, BF849365, Z42201, AI095571, BE834137, AA360151, H71618, T52688, AW363353, BE770047, BF850276, AA555002, AW845124, BE933555, BF850265, H10415, Z38453, AA972682, AW580913, AA151080, AI687810, BE928875, R60991, H67823, BG004415, AW905113, AL035760, BF765364, BF086245, AA484675, R43800, BG179430, BG232027, BG256537, BE928869, BF922448, BF822727, D87446.1, AK025852.1, AC004072.1, AL133321.11, AC012067.2. HHFEC39 103 609873 1-1288 15-1302 BE178297, BE891680, BE178296, BE178286, BE177969, AI817262, BE178117, BE220165, AW025400, BE178101, AI377829, C06099, BE178000, BF940116, AI422898, AI089906, AA583355, AA971743, AA044947, AA044943, AI076496, AI299481, AI376081, AA427892, H98616, AA618566, AA532381, AI080656, AA884934, AW341785, AA730790, AI139706, AW139974, AA992454, N99650, AI094082, AA483691, AA482694, D62553, AA001089, AI205651, R80152, Z36959, AI692586, AW958955, F10610, AA516076, AI311975, AI313288, AI379372, AI348747, D62481, AI610907, AA513037, AI611925, AI784325, BF054671, D62330, BF054866, BF057878, AA149057, N71679, AA923038, AW969749, BF364372, R43511, D62106, D79281, N83844, T75442, BE168027, BE936283, F13013, BE043482, AI348789, D62153, BE168085, BE178420, BE177858, AL022726.1. HHFFS40 104 824059 1-1802 15-1816 BE877462, BF792909, BG260156, BG179110, BG112928, BF980559, BE544254, BG170563, BG107623, BF345994, AI763152, BE566242, BF346074, BF672687, AW299766, AI809063, AI658640, AW956747, BG256039, BG255904, AA630311, BE958056, BE873360, BE858485, AW072428, AW590087, AW996985, BE786419, AW963580, BF694200, BE565358, BF669441, AI521984, BF210963, BE564370, BG254405, AA554914, BE877693, BE872103, AI802337, BF242746, AA837003, BE674128, AA704063, AI697970, AI360303, AA676411, AI335019, BF940184, AA758569, AI341577, AI368085, AA976338, AA131990, BF594262, W52093, AI400190, AV655671, AA776953, AI720984, AI969963, BE538461, AI652576, AI924939, AI281274, AA610809, BF999637, BE540644, BF185031, BE564453, BF217183, AA599513, W60435, AI364496, AA622238, BE564859, AA173574, BE564942, AW181884, AA486013, AA452454, AI377701, H57481, AA775104, AA809861, BG110906, AI096469, R22549, AI948687, BG170098, AW467467, BF666042, AA136404, AI914432, AI952665, R72480, W19427, AI651051, R63250, BE768905, AA532466, BE564416, N92774, BE866100, AA487194, AA191014, AA436377, AA419582, N24149, AW072184, H99384, AW962785, AW731695, W52957, AA885982, AA136214, AI000422, AA885090, R73256, AA721779, W59973, AW273180, AI969516, AW996746, AA648637, AW572880, H26458, AA775095, R93450, AA721131, AI866701, BE929433, BF185491, AW129228, AW181995, R80927, AA629087, AV725677, AA486839, AA809868, R64668, R63022, BE247146, BF434557, AW381266, AW129216, D79097, BE925523, AA612598, R93403, AA370728, AA564131, AA330516, AA629088, R62968, AA564772, BE047336, R24143, BF808222, BF807139, AA876640, H58002, AA384569, AW261840, AW361037, AA099083, N40700, AI926874, N27938, AA513948, BF246298, AI499459, BF211955, AW857210, D60986, AA219670, AA247626, AA935365, H58409, AA829160, AA383046, BF960785, AA381919, R14311, BF748705, BE087099, N54068, BE769764, N56083, BE169239, AI583038, AI701882, AW193574, AI886791, AW080675, AA131685, BF954179, T10637, AI619990, AI866695, AI520974, AI446785, AA173533, AI953438, AA746406, BE540062, BF960843, BG014707, BE092961, AA604836, BE720113, AI358254, AI445976, AA190478, BG015664, BF760985, AI634805, AI254727, BF812938, BG110684, AI263312, BG165051, AI554218, BF871413, AI961589, AI915291, BG249582, BE047852, AW026882, BE965621, BF969126, AI637584, AW022699, AI566670, AI590423, AI274759, AW268067, AL514457, BE536058, AI568138, AI431909, BF811804, BF856017, AW104141, AL133078.1, AJ296152.1, AL133113.1, AL389939.1, AF090943.1, BC003682.1, AF262032.1, AK026741.1, AL137527.1, AL162083.1, AL122050.1, AB047904.1, AL512689.1, AL442082.1, AK024538.1, AL133557.1, AL136784.1, AF090900.1, AB060912.1, BC001967.1, AL442072.1, AK025339.1, AL080124.1, AL117585.1, AF146568.1, AL389982.1, AB055361.1, X53587.1, BC004529.1, X69819.1, BC004958.1, AK026542.1, BC008387.1, S61953.1, AF078844.1, S78214.1, BC008893.1, BC004533.1, AF090901.1, AL512718.1, AF090934.1, AK000432.1, AL122045.1, AF207829.1, AL136892.1, AK026045.1, AB055374.1, AB056420.1, AF090903.1, AK026504.1, AL136850.1, AK026526.1, AL050149.1, BC002733.1, AF106862.1, AF104032.1, AL137526.1, U58996.2, AB048954.1, AF125949.1, AL122110.1, AB055315.1, AK025967.1, BC002454.1, BC008417.1, AB055303.1, AB060887.1, AF125948.1, AF061573.2, AB048994.1, AB049900.1, AK026583.1, BC006164.1, AB060873.1, AL133665.1, AL512746.1, AL512719.1, AF057300.1, AF057299.1, AK026480.1, AL049382.1, BC006103.1, AL359596.1, AL080127.1, AL133016.1, AL353956.1, AL050393.1, AL133080.1, AK025391.1, AJ299431.1, AL096744.1, BC008280.1, AL136844.1, AB055352.1, AL136845.1, BC007021.1, AF230496.1, AB049892.1, BC008983.1, AL050116.1, AL359941.1, AB047887.1, AK025312.1, AL137705.1, AL162006.1, AL117460.1, AK025798.1, AB056809.1, AL110221.1, AL117394.1, BC003687.1, AK027213.1, AK026647.1, AL137538.1, AL080234.1, BC003683.1, AL136843.1, BC008899.1, AL136749.1, AL512684.1, AB063070.1, AL110196.1, AB048913.1, AL137459.1, AL137533.1, AL136789.1, AK026927.1, AB049758.1, AL050108.1, AL389935.1, AB049848.1, AL136799.1, BC007389.1, AK026959.1, AL117435.1, AL136928.1, AK026642.1, AB055366.1, AK027164.1, AK026630.1, AL122098.1, AK000391.1, AL133565.1, AK000614.1, BC007326.1, BC002798.1, AK025435.1, AK026506.1, BC006195.1, AK000718.1, BC008488.1, AF091084.1, AL137429.1, X82434.1, AK027096.1, AL137557.1, AL133558.1, AF217966.1, AL049314.1, AK026744.1, AB063046.1, AL137550.1, BC006472.1, AK025632.1, AK000753.1, AL359601.1, AL136768.1, BC006525.1, AL157431.1, AL512765.1, BC004556.1, AL080137.1, BC008365.1, AK024524.1, AL133067.1, AL390154.1, AF073483.1, AB062942.1, AB052191.1, AL049452.1, AL137560.1, AL133640.1, BC004362.1, AL359583.1, AK025084.1, AK025092.1, AK026551.1, AB048975.1, AL137548.1, BC002523.1, AL117457.1, AK026452.1, AL359618.1, AF352728.1, BC004368.1, AL136586.1, AF090896.1, AF162270.1, AK026600.1, AL122093.1, AL050138.1, AL110222.1, AL050015.1, AF097996.1, AL136615.1, BC005151.1, BC004530.1, AB060929.1, AB055368.1, Y14314.1, AK000323.1, AK025484.1, BC006133.1, AK027116.1, X72889.1, AF358829.1, AL133093.1, AB048953.1, AB047930.1, AL512754.1, AL137271.1, AL133075.1, AB048974.1, AL136864.1, AF321617.1, AY026527.1, AL137300.1, AL136787.1, AF061943.1, AK026865.1, AK026855.1, AK000618.1, AF218014.1, U39656.1, AB060863.1, AB060908.1, AJ242859.1, AB047801.1, AK025573.1, AB063077.1, AK000450.1, BC000348.1, AK026592.1, AL050146.1, AY034001.1, AF056191.1, U42766.1, AL133606.1. HHGCS78 105 634605 1-561 15-575 AA523300, AI962903, AA528118, BE858430, AW083553, BE858714, BE893836, AI190409, BE856210, AA769649, AI693556, AI366045, AI609800, AI337942, AW769813, AA613831, AI051792, BE874678, AI799232, AA682810, BE769324, AI810459, BF689177, BF593003, AA705587, BE896233, AI421592, AI421946, AI421527, BE731882, BE855826, AW817923, AI962361, R79580, AA581733, AI342639, AA649978, AI984920, AI624953, AA682704, AW802785, AL119863, BG163618, AL120853, BG029667, AW059828, BF814420, BF792961, AI358701, BF904265, BF338002, AL134259, AL042627, BF970658, AI815855, BG033723, BE393551, BG180996, BG026447, BG114104, AW827206, AV682264, AW411235, BG165051, BF970768, BF970652, BG030364, BF692486, AL038445, AW827103, AV708893, AV709314, AI334445, AV656478, AV684604, AV755884, AL041772, AL039086, BF752245, AV727029, AL043070, AI538764, BG181012, BG058150, BF854113, AV714274, BE876049, AV713662, AV756026, AV647773, AA100772, BG122481, BG105895, BF924882, BE895585, AV729189, AL048656, BF726207, BG113224, BG256880, AL041150, AI312428, BG112718, AV682791, BE966479, AI932794, BE966699, AW129271, AW827227, AW169653, AA508692, BF527014, BF971016, AA853213, AL046463, BG151388, BG105473, BE874133, BF969126, AL036980, AA853539, AL119791, AW301409, AV648263, BG260037, AI073952, BE785868, BE965067, AW238730, AW020095, BF343286, AL045266, AL513907, AI538342, AW827203, AI568114, BE885353, BF752836, AI309401, AL514627, AI784230, AW022682, BF970449, AI554343, BF032768, AI637584, BE885490, AW673679, AI284517, AI932915, BF921103, AI335426, AI348777, AW172723, AI791396, BF312128, AI922561, BE018711, AI344785, BE826053, AV681848, AA420758, BE964614, AI818574, AI671642, AW265004, AL037454, BG027082, AL038605, AW163823, BG029086, BG164558, BE172689, BF061283, AL036274, AV655645, AV647118, BG178689, AI340511, AV682466, AW161579, BE965724, BE779152, BE881005, BG112879, AA427700, AW079818, AI783504, AW827289, BE047852, BF339322, BG029053, BG168185, BE965330, AW238688, BF313411, BG260187, AV755484, BE047952, D50977, N99092, AL042400, AW410969, BG109140, BF672397, BE965192, AW834302, AI866573, AW806761, AL119836, BE837422, BE963838, AL037582, AL037602, BF798503, BF753013, R36271, AW268067, AL079963, AI335208, BG249582, BG179993, BF904193, AI491852, BF968027, AW302992, BE875407, BF038804, AI499986, AI630252, BE965481, AV715359, AW149092, AV743631, BE884296, AV733385, AV758087, BG107410, AI343059, AL079741, AL042628, BF910810, BF909758, AV703169, AW303089, BC005084.1, AF001552.1, AC006221.1, AC073042.7, AC015982.9, AC007458.13, AC083867.4, AP001711.1, AL139099.2, AL355382.6, AB019438.1, AL356800.3, AL389939.1, AL136893.1, AL137527.1, AK027114.1, AL138755.13, AL512761.1, AL162008.1, BC004951.1, AK024538.1, AL080137.1, AL050024.1, AK024588.1, AB060826.1, AK026506.1, AK025254.1, AL136586.1, AL080124.1, AL049430.1, AL359583.1, AF260566.1, AK000718.1, AK025391.1, BC006508.1, AK025375.1, AK026762.1, BC006201.1, AL136749.1, Y16645.1, AB055315.1, BC006440.1, AL050172.1, AK025092.1, U91329.1, AB060912.1, BC008417.1, AK026608.1, AK027113.1, AK000618.1, AL137526.1, AF090943.1, AL133640.1, AL359601.1, AF090900.1, AL133014.1, AL162083.1, AB052191.1, AK026583.1, AL136844.1, AK025491.1, AL136789.1, AL133565.1, BC005168.1, AK027200.1, AL133075.1, AF061943.1, AF162270.1, BC000090.1, AL136754.1, AL389935.1, BC007326.1, AL359596.1, AL117583.1, AL133557.1, AK025632.1, AB060852.1, BC008893.1, AF056191.1, BC008488.1, AL117578.1, AK027142.1, AL157482.1, AK026591.1, AL137476.1, AB048953.1, AK026526.1, AB060863.1, AK025414.1, S78214.1, AL136780.1, AK026600.1, BC006195.1. HHPFP26 106 753269 1-2338 15-2352 AW955777, AU127795, AV699578, BE621969, AI346748, AI281940, BE005208, AA524503, AA916758, AW449058, BE467769, BE464881, AU151450, BF514115, BF000038, AI634820, AI523530, AW511445, AI862532, AI949670, AW970765, AA608828, AI857780, BF571416, AW295536, AI377542, AI093088, AA287191, AI151251, AW614038, AA287100, AV699485, AA448285, AW770401, BF737449, AA878147, AW337811, AW593438, AI094118, AI679170, AU129292, AA824653, AA126509, AI335819, W17300, AA724997, AI926067, BF445215, N89777, AI376326, BF898929, AA693394, H24089, W20017, AA780601, AI262511, H95444, AW023522, BF330087, AW605999, AA651916, AA708871, BF968034, AW380437, H95445, R43926, C03566, AW452210, R18816, AA334867, R84237, N91375, AW020824, H22911, W24107, D62482, N91929, D62471, AW630974, BF946583, BE708592, BF195756, AA658355, AI962246, AA282731, BE967075, AL136581.1, AK022861.1, AK023008.1, AL163853.4, AL157911.4. HHPFU28 107 824573 1-1824 15-1838 BF035537, AW069711, BF672434, BE883242, AI656112, W31606, W07084, AI272643, AW170657, AA166968, N77917, AW513307, W15523, C75056, AA167046, AA228908, AA228890, AA856550, BE540895, AA856549, AA883954, AI636144, F16318, AW275622, F15813, AA629229, AW979328, BE825903, AA683173, AW954221, AV725561, AV703624, AW962970, AV646649, AB002332.1. HHSBI06 108 639097 1-1035 15-1049 BE676485, N59786, AI920783, AA088744, AA779158, BF438300, BE645431, AI915060, AF271897.1, AF285442.1, AF051651.1. HHSBI65 109 801910 1-1430 15-1444 BE796723, BE541989, BF057278, BF063128, AI990159, AW003665, AW300907, AI738928, AW246641, AW594304, AI521438, AI394059, AA994208, AI130030, AW083104, AA811418, AA974513, AA761013, AA765652, AI583684, AI748894, R67183, AA483531, AA836959, AW236517, H29649, BF115987, AA747573, AA434041, AW845318, T75095, H29565, BE742632, BE386466, AW196291, AI608701, F10461, BE385745, AI474368, BE502390, BF115569, BG236177, BG230771, AI825041, R54830, AW117865, R38529, AA370939, R43648, AA215393, BE552433, AV749164, BF112242, F13491, BF058839, AI087969, AA215394, AI475583, AW450912, T25126, AA434109, AK026541.1, AF174592.1. HISAT67 110 843549 1-2140 15-2154 AL519801, AL520029, AL521674, AL515614, AL519807, AL519808, AL526569, AL519802, AL520030, AL535434, AL521675, AL515615, BE798433, BE797403, AL528668, AU130192, BE745046, AL535433, AW177988, AW177985, BF526765, BE741361, BE546284, BE882894, BE745446, AI924136, AL524747, BE902340, BF796576, BF314225, BE622034, BF237909, BE257929, BF306879, BE617643, BE867904, AW374088, BE617000, BF688830, BF345850, BF688351, AW960985, AA252420, BF817742, BE622673, BE535410, AI183729, AW438568, AA769320, BF816143, BF541658, AI274790, AA058936, BF530326, BF345429, BE568171, BF315183, AA827859, AI150987, BG104230, AW192463, BE383533, AW769453, BF195400, BG253720, AA699494, AI298600, BE395450, AA411591, AA976201, BF246062, AA565575, AI811947, BE838606, AU155423, AA425979, AA548944, AI096361, AA151497, AW087834, AI361378, AI085749, AW027881, AA426271, AA613326, AA687138, N81134, AA411464, BG222316, N35214, AI299858, AA394068, AA088263, AI150914, AA889019, AA252504, H83961, AL045552, AI689551, BE819030, AI089337, BE565997, AI803858, AA151552, AU134447, BF347858, AW247185, R40419, AA351639, H58370, AI362586, AI631415, AU157064, AW406063, R69998, BF132861, AA292350, H06495, R13035, AI858744, AW392518, AW517903, AI539838, BG169732, AA564447, AI280222, AU137181, H58371, AA355297, H11618, R74275, AW606537, BF825915, AA478985, BF914457, BF247267, N90293, AA324676, BF913845, W04666, BF695749, R39793, AI932851, AA629936, AA300144, AW731758, AI886965, AA477921, AA580861, AA632377, AW957318, C02190, AW089325, AW402477, R37205, R31157, AI633079, R12741, T34011, BF527821, BE819060, BF761740, AW139230, AI369955, AI579955, BF244267, R74188, R27176, Z17827, BF874647, AA877093, BE819032, AA582577, BF435602, F32545, N75291, N99252, T25048, AA467840, AW392536, AA467896, AW968190, AI085046, AA151496, H83960, AA468217, AW607357, AW631248, AW051088, AI360195, BF792469, AI610402, AI249946, BF753056, BE069307, AA514684, BE909285, AL042544, AI921167, AI002285, AI815855, AW163834, AA888196, BG029053, BE047833, AI698391, BF927081, AI923989, AV756026, AW118508, AI887775, BE965481, BG121959, BF813196, AV756182, BG029667, AI582932, AW059828, AL037454, BF814761, AV681848, BF726183, AA830821, T99953, BE877142, AW009306, AW161098, AA420722, AI452857, BE245461, AI345745, BF969807, BF918076, BF921291, AV735098, BF529088, BE536263, AV708119, BF529870, AV727839, BE964614, AI500061, AI696626, AI633125, BF885000, AI915291, AF203687.1, BC002765.1, AF226684.1, AK023064.1, BC008658.1, AF227166.1, AK023405.1, AK001976.1, AF125949.1, AL133560.1, AL359618.1, AL110225.1, AF090901.1, BC008488.1, AB049892.1, AB047887.1, X86693.1, BC003548.1, AL133080.1, AL110221.1, AF091084.1, BC008387.1, AB051158.1, AK000323.1, BC004310.1, AF090903.1, BC006201.1, AL133606.1, BC004297.1, BC002975.1, AY033290.1, AL512689.1, AK025484.1, AK026462.1, AK026528.1, AB060863.1, AK026480.1, X72889.1, AK026542.1, AL512750.1, AB063070.1, AB056809.1, AK026504.1, AF097996.1, AL050024.1, AL122050.1, AK026583.1, AL049314.1, AK000083.1, AL137533.1, AL117394.1, AK024538.1, AL133640.1, AK027142.1, BC004556.1, AF106862.1, AL049464.1, AL137560.1, AK026744.1, AL137538.1, AB048975.1, AK000486.1, AL512733.1, Y16645.1, AK025967.1, AK027160.1, AL117435.1, AL137550.1, BC006807.1, BC004908.1, AL122110.1, AB060826.1, U39656.1, AL133081.1, AB055366.1, BC004958.1, AK026927.1, AL050146.1, AL137660.1, AF078844.1, AK027113.1, AK027096.1, AK025092.1, AF217982.1, AL136792.1, AK026434.1, AL137480.1, S78214.1, AK000445.1, BC001967.1, AB060832.1, BC001045.1, AL117585.1, AK026534.1, AK000614.1, AL137283.1, BC008899.1, AF069506.1, AK026959.1, AB060908.1, BC003682.1, S77771.1, AK000291.1, BC003684.1, AL096744.1, AL050393.1, U42766.1, AL133031.1, AL136805.1, AC068715.5, AK026647.1, AB055361.1, AK026353.1, AL050277.1, AL049430.1, AK026164.1, AB062938.1, AK027081.1, AF090886.1, AK025772.1, AL122093.1, AB052191.1, AL122121.1, AC025226.4, AL136799.1, AB019565.1, AL137429.1, X82434.1, AF090934.1, AF090943.1, AL137557.1, AB048953.1, AF277181.1, AL512684.1, BC008284.1, AL136786.1, AB047615.1, AK026642.1, AK025339.1, AL137271.1, BC005168.1, BC008844.1, AK025209.1, AB056420.1, AK026784.1, AK027200.1, BC006525.1, AL117457.1, BC009355.1, AF260566.1, AL157431.1, AL512765.1, AF146568.1, AL136845.1, AL133113.1, AL137527.1, AL133565.1, AL136784.1, AF232009.1, S61953.1, AL035458.35, BC007326.1, BC001774.1, AL136640.1, BC007548.1, AK025414.1, AK027204.1, AK025491.1, AL359601.1, AL133016.1, AK025708.1, BC004119.1, BC009113.1, AL442072.1, AL353940.1, AL353956.1, BC008004.1, AB055315.1, AL137555.1, AJ012755.1, X98834.1, AX026608.1, AL137300.1, AK000652.1, BC002978.1, AL162003.1, BC006164.1, AB048954.1, AB060916.1, AK025632.1, AL133077.1, AF111847.1, AJ010277.1, AL049466.1, AL137548.1, AK026526.1, AC019176.4, BC009010.1, AF225424.1, AK024588.1, AL512754.1, AB050534.1, AL353957.1, BC004951.1, AF177336.1, AL359596.1, AL136844.1, AB063046.1, AB048974.1, AJ242859.1, AB060857.1, AB060852.1, Y14314.1, AL050116.1, AL050108.1, AL136825.1, AL137521.1, AL122123.1, AF230496.1, AK026506.1, AK000212.1, AK025383.1, AC069298.8, AL136790.1, AL162002.1, AF026816.2, AK027114.1, AL389939.1, BC003687.1, BC002647.1, AK026741.1, AF218034.1, AL512746.1, AB060825.1, AL136843.1, BC008719.1, AB055303.1, AB060887.1, AF090900.1, AK026452.1, AB049758.1, AL442082.1, AL133047.1, AK026551.1, AF106934.1, BC004191.1, AL389982.1, AC005876.3. HISBA38 111 561711 1-1044 15-1058 AA465219, AW968392, AA465303, AL042753, AV759518, BF868994, BG029528, BF725761, AI963720, AL037683, AA129746, AL041924, AV682003, AV763460, AL138455, AL079734, AV757289, AI282253, AA669155, BF827410, BE252421, AL042853, AV760391, AA760655, AL079447, AV760389, AV762395, AA551105, AI049643, BG164617, AL137020.13, AC006581.16, AL122023.3, AL022322.1, AC007436.1, AC004706.1, AC068722.6, AB045357.1, AL035552.9, AP002532.1, AC022324.5, AL121869.19, AL109752.13, AC020559.4, AC008901.5, AC006017.2, AL354943.9, AC073897.6, AL353752.6, AL121823.12, AC005798.10, AF117829.1, AC018719.4, AL138832.10, AC010722.2, AL358612.8, AL163206.2, AL138879.10, AC090710.16, AC005250.1, AL365222.24, AL163213.2, AL133517.11, AP000493.1, AC005539.1, AL139150.12, AC003029.2, AC008766.4, AC009316.3, AC005002.2, AL133244.1, AL137818.3, AL031433.4, AC010081.4, Z97985.16, Z94722.1, AL590611.7, AC025253.20, AL137918.4, AL121652.2, AC073881.3, AC004998.2, AL355834.4, AL450345.6, AL163201.2, AL137840.12, AL049835.3, AL355143.17, AC006466.3, AC002457.1, AL132827.2, AC090957.1, AL049697.9, AL109939.13, AL133373.5, AC068723.5, Z98754.1, AL356278.8, AL355535.14, AC087315.21, AF212831.2, AL023876.2, AL359234.4, AL390205.17, AC007683.5, AC010140.3, AP002448.3, AC034148.9, AC027129.5, AL357272.10, AL023279.1, AC012372.4, AL022152.1, AC006287.1, AC006313.1, AC019155.4. HJBCU75 112 638329 1-995 15-1009 AA789332, AI925535, AW469963, AI925543, AA312696, BF732842, BE670545, AI685010, AW962841, AI690167, AA570056, AA470465, AW969303, AW770920, AI634463, T95424, T95333, AW080646, AW003925, BE617765, AI468303, AA311608, AW268987, BE669814, AA356443, BF690832, AW753521, AA682679, BE962309. HJMAA03 113 824062 1-651 15-665 AW304711, BE677684, AW959142, AI290480, BF090788, AW571568, AI092037, N55492, BF090740, W05027, BE714108, N76979, AA361785, N70383, C02489, BF987194, BF087284, BF087325, AA732983, AI348883, AV682863, AW305097, AV691827, AL038473, AW265139, AL442128.7, L44140.1, AC004867.5, AC004166.12, AC009996.7, AL135905.6, AP000087.1, AL158158.14, AC018809.4, AF190464.1, AL391839.9, AL035684.25, AC007172.6, AP001694.1, AC009753.5, AC007383.4, AC026431.3, AP001623.1, AC002558.1, AC068533.7, AL133243.1, AL161670.4, U52112.1, AL135839.15, AC084864.2, AC005180.2, AL359265.8, AC020716.3, AF287262.1, AC024082.6, AC002551.1, AC010267.6, AL160471.5, AC004883.2, AC007225.2, AL359091.10, AC020663.1, AP001710.1, AL121972.17, AP001746.1, AC006111.3, AC079684.16, AL035086.12, AL031670.6, AL135744.4, AL391827.18, AP002515.3, AC005098.2, AC018639.8, AC087071.2, AC002565.1, AL354932.26, AL160269.14, AC087244.17, AC004491.1, AC018751.30, AC083884.6, AC007308.13, AC083868.2, AL031587.3, AL035458.35, AC004878.2, AC004832.3, AC002316.1, AC003950.1, AC006486.1. HJPCH08 114 840365 1-865 15-879 AI655312, AW975835, AI653243, BF059498, AA731744, AW590208, AU154664, AI671173, AI669341, BF970492, AA704870, AI654412, AI889336, BE966747, AI739117, AI168283, AA781842, AI203090, AW383906, AW103151, AW589549, AW074368, AA600977, AI014854, AA179845, BE775064, BE090424, AA630744, AV714379, AW857113, AW075406, BF982048, AA736497, AA789069, AW770138, BE696241, BE622755, AW074752, BE928343, BF762364, AI904387, BE539952, AA471345, AF153329.1, AF070672.1, AK024804.1, AK025790.1, AC004826.3. HKABU43 115 838573 1-1905 15-1919 BG035820, BG163860, BE779136, BG032640, BE546300, BG251357, AI890545, BF798002, AW957817, AW957894, BG164329, BE897914, AI064868, AW439699, BE868957, AI628884, AI538687, BG117638, BE075026, BE075028, BE877956, AI890859, AW241402, BF057808, AI962251, BE672376, BG254061, AI655998, W76094, AW593934, AW206368, AW070698, BF592891, BF855200, AI913939, AW242743, BE892303, W72889, AW510467, BE502137, AW852201, AW468485, AW242300, BE073158, BE073145, AI370901, AA076346, BE075023, BF761114, AI269861, BE927867, Z19251, BF229820, AA912859, AI962408, AA449269, BE869764, AA449405, AI125399, AI766912, BG230901, BF761369, R82858, BE927921, AI651447, AW852191, AW874171, AA313460, BE268347, AI440431, AW603030, AA322088, BE503487, AA373986, BE927954, BE677880, BE816387, BF679224, BE816422, BE927027, BF514420, BE297845, BE390905, BE535739, AV762904, AA564527, H29863, BE743929, AA369997, AA370398, AW957044, AA852197, AB018262.1, BC003633.1. HKIXC44 116 716213 1-774 15-788 AL523457, AL528447, AL523456, AI829517, AW149466, AI583221, BF939526, AI421289, BF062158, BF939874, AI279154, AI418427, AI703444, AW131506, BF571573, AI936825, AI089933, AI361161, AW014685, AI536856, BF476644, BE047689, AI369406, AW021011, AI457455, AI302724, AI354478, R61374, AI079090, AA120924, AI362672, AW118437, AW178756, BF447506, H45647, H18233, AW023679, H18271, Z25058, AI361962, AA974813, AW079462, AW089212, H41457, AW970953, AW873883, BE939242, BE151736, AA664017, AA120923, H40869, BE762902, AF176422.1, BC001873.1, AF232239.1, AF151522.1. HKTAB41 117 695732 1-783 15-797 AW269751, BE046932, AI962247, AI652884, AI336991, BF592937, AI632408, BG260037, AI611738, AI784252, AI633419, AI863382, BF343172, AW163834, AI927755, AI500061, AI783997, BG256090, AI470651, AI571909, AI829327, BE535358, AW162189, BF342070, AL036980, BF828567, BE544111, AI886415, BE965031, BF792961, AI590120, AI918655, AI569583, AI288285, AI554821, AW059713, AW148716, AI648684, AL079963, BE047852, AW268122, BE048071, AI569309, AI698401, BE910373, AW148970, BE047737, AW089664, AI784230, BE538997, H89138, AW827289, AI916419, BE895585, AI468872, AI358701, AW105601, AA427700, AI886192, AL041150, AI269862, AL514129, AI345347, AL037582, AL037602, AW131308, AI863321, AW149227, BF727034, AI343059, AI251221, AI349933, BG035511, AI345608, N80094, BG166654, AI922901, AI345253, AW827227, BF527014, BG029053, AI500662, AI348854, AI345471, BG179993, BE965355, AI869377, BG115626, AI679179, AW827106, BF970768, AI590686, AI471361, AI873644, BG031539, AI174394, AI933589, AI635067, AI565128, AV702623, AL036403, AA908294, BG250190, BE620444, BE964812, AI921248, AV743962, AW169604, AL047675, AI282679, BF856017, AI886753, AL121286, BF794018, BE536058, AI801325, BF854113, BG109270, BG165979, AI431424, AI445992, AW029275, AI699011, AI874166, AL036638, AW088903, BG031664, BG120816, BG168696, AL514691, AW268302, BE907440, AW072719, AI589267, BF816037, AI611348, AW059828, BE965724, AW827103, AV710608, BF920893, BF814527, AW118496, AI499986, AW117919, AI826225, AI811785, BF816042, AI681985, AA225339, AW054931, AW196299, AI619502, AI680162, AI478123, AI677796, AI802542, AI352497, AI439717, AI288305, BF672397, AI284131, AW118518, AW023590, AI499285, AI863411, AW983829, AW050578, AW148356, BG249582, AI570807, AI306705, AI824576, AW169653, AW026882, AI470293, AI923370, BG058150, AI312428, AI159837, AI613436, BF812960, BF812938, AI950664, AI537960, BG164558, AI582932, AV727776, BF970652, AL042628, AI520809, AI637748, AV746964, BE789764, AI537303, BG027280, AI521560, AW089350, AI497733, AI433157, AI702073, BF089711, AI569975, BE047732, AW188554, AW183130, AI567582, BF812961, AI500523, AL037454, AI683492, BE874133, AV699198, AW117746, BG179633, AI683173, AI445165, AI963216, AI863082, AW102761, AI564749, AW051088, AI282326, BF814420, AW172723, AI868204, AI633125, AI888522, BF680133, AI887247, AI698391, BG122481, AI869367, AI612885, AI783504, AL036214, AC006451.5, AC007056.4, AC006013.3, AL445528.16, AP000344.1, AC004057.1, AF131216.1, AC007597.3, AC004837.1, AK026504.1, AC006501.5, AL050092.1, AP001731.1, AL389939.1, AL133075.1, Y16645.1, AK026533.1, AL583915.1, Z99495.1, AK026462.1, BC005890.1, AB063070.1, AL512750.1, AK024538.1, AL389982.1, AL12121.1, AL122123.1, AL121916.14, AL157431.1, AL390154.1, AF353396.1, AL137550.1, U39656.1, BC005168.1, AL136805.1, AF078844.1, AL080124.1, AK025209.1, AL110221.1, AL512765.1, AL117435.1, AK026408.1, AL122049.1, AB055374.1, AB047801.1, AK027868.1, AL080159.1, AB060916.1, AK027160.1, AF090903.1, AK027164.1, AK026464.1, AL049452.1, AK000432.1, BC001045.1, AK000486.1, AK025798.1, AB063079.1, AL136864.1, BC008387.1, AL162008.1, AK027096.1, BC002839.1, AK000137.1, AF162270.1, AB055303.1, AL359601.1, AB060887.1, Y14314.1, AL157482.1, AK026593.1, AF146568.1, BC008365.1, AL117432.1, AL137292.1, AL136749.1, AL137476.1, AL512718.1. HLDBG17 118 855953 1-638 15-652 BF002740, AW015349, AW172836, N51711, BE619681, AA620652, AA639043, AA447223, AA648349, AL048032, D62490, BE930019, AI973069, AI370576, AI889304, BF885813, AW975098, BF377527, BF885812, AI370615, Z41325, BF885814, R39086, AA658236, BE708124, AF131793.1. HLDQU79 119 740755 1-1474 15-1488 BG256275, BE867624, BE907396, BE855521, BF034422, BF530803, AW959247, BE782005, AI126689, AL121446, AA757065, AW630129, BF768037, BE746763, AA206154, AA460401, AI276320, BF998689, AA295243, BE242732, BG035901, AL040350, BE242810, T86168, BF983867, W05088, AA347337, BG252443, AI133502, AF064093.1. HLHAP05 120 638476 1-1828 15-1842 AW963016, AW979070, AA554869, AA828610, C14699, AA359181, C15123, AI380617, AW303196, AW301350, AW023111, AW974639, AI798545, AA359849, AV711430, BE252421, BG222813, BF974349, BG236628, BF804385, AI246796, BF918155, AV711465, BE180633, AW327868, BE301584, BF879045, BF965775, AA574442, AI253987, AW410784, C15415, BF761328, AI357823, BE676019, AV738383, AW270258, AW167330, AA610509, AI188390, BG029224, AV759972, AL117335.26, AL109976.23, AC009087.4, AL136081.10, AL021579.1, AF064861.1, AC079684.16, AL163279.2, AL136000.4, AC006014.2, AC005067.2, AL049839.3, AL035587.5, AC008569.6, AL513131.1, U89335.1, AC008771.4, AC005052.2, AC073136.6, AC003104.1, AL117336.22, AL031730.1, AC022515.5, AC009570.13, AC010328.4, AL049776.3, AL135749.3, Z85986.1, AC002369.1, AC007201.1, L44140.1, AL133545.10, AC011450.4, AC013726.7, AL034405.16, Z84469.1, AL139099.2, AL136305.14, AC020908.6, AC005291.1, AC008622.5, AC004647.1, AL158040.13, AC018636.4, AC008625.5, AC005488.2, AL050307.13, AC083863.2, AC007969.3, AC016602.6, AC002316.1, AC010126.3, AL359235.3, AC006480.3, AC004819.1, AP001748.1, AC006157.2, AL121969.12, AC003093.1, AC011236.8, AC009362.8, AC018648.5, AP000924.6, AC005261.1, AC004520.1, AP001705.1, AC008280.4, U47924.1, AC018695.6, AC004000.1, AL049646.19, AC002425.1, AC011005.7, AL359711.18, Z85987.13, AL132659.10, AC004953.1, AC006329.5, AC016594.6, AC011465.4, AC073321.4, AP000240.1, AC007308.13, U95742.1, Z97056.1, AL049761.11, AL391241.21, AP002852.3, AC025679.4, AP000424.3, AP000096.1, AL031311.1, AL034420.16, AC005098.2, AC009086.5, AC026464.6, AC002350.1, U91318.1, AC007664.12, AL020995.14, AL354813.31, AC083866.2, AC004797.1, AC004791.1, AC002504.1, AC005722.1, AC022211.5, AC009068.10, AC022405.5, AC005932.1, AC025457.5, AF318296.1, AC005077.5, AL161670.4, AC004815.2, AC027129.5, AC012170.6, AC011894.3, AL121586.31, AF287262.1, AC006530.4, AC022415.5, AL162293.22, AL117352.12, AL121891.22, AC007216.2, AL034451.26, AC009244.24, Z97985.16, AC006006.2, AC011247.10, AL132713.11, AL133246.2, AL135818.3, AJ400877.1, AC004098.1, AC004922.2, AP001670.1, AC010618.7, AC009137.6, AC011551.3, AC002470.17, AC011737.10, AL353668.18, AC079361.17, AC007421.12, AC005520.2, AC005082.3, AC005099.1, AL035659.22, AL445928.8, AL136300.22, AF243527.1, AC005940.3, AC019205.4, AC024561.4, AC004655.1, AC005562.1, AC004656.1, AC072061.8, AC016995.4, AC015853.8, AC004222.1, AC005531.1, AL354816.5, AL157372.18, AC006483.3, AF168787.1, AC012151.13, AL109935.39, AC006211.1, AC004128.1, AL035088.1, AC005952.1, AC011453.4, AC004648.1, AL133228.18, AC010913.9, AC007371.16, AC007030.3, AL121972.17, Z95152.1, AC000134.14, AC034198.6, AC007690.11, AL117382.28, AP001630.1, AL162430.15, AC006452.4, AL589723.7, AL009181.1, AL121992.24, AL132768.15, AL445490.6, AC008072.3, AC007220.4, AL132640.4, AP000210.1, AP000132.1, AC068724.7, AC004702.1, AL359792.3, AC004216.1, AC006509.15, AL049636.22, AC011816.17, AC008397.7, AC020916.7, AC010326.6, AL162464.5, AC005378.2, AC069262.24, AL031905.7, AF288742.1. HLHBS54 121 837503 1-4024 15-4038 BE793391, BF037440, AW411431, AW411432, AV723798, AL118640, AA421652, BG028281, AI141739, BE296303, BF980969, AA569352, BE729319, BE619348, AI093588, AI056382, AI751145, AI830945, AW959700, BE746540, AI978744, AA203147, AW385187, N36100, AI131280, BF058207, AW385194, AW964924, BF996174, BE895496, AI697330, BF855572, BE298675, AA572769, AI431821, AI306411, AA129607, BE910210, AI270378, AW675183, AA284276, AI697452, BF943592, AA613934, AA459541, BF205506, AW580438, AI591380, BF943589, BE295387, AI830868, AI521845, BE783079, AA613025, W79827, AI658493, AA658343, BF943544, AI658483, AI640733, AA453151, AA171976, AA180412, AI066480, AA179828, BF858120, BF943550, AA464519, AI074418, AI827350, AI818147, AI079578, AA180376, AA970308, AA569579, AI038151, W78160, W07621, R53199, AI431691, AA180411, AI266113, AW390238, N24863, AA227163, AA612938, AA641053, AA172124, N90891, N31800, AA464520, BF931838, R54307, AA459310, H44552, AA084338, R51916, W46679, BE616851, R78942, BF943548, AA421653, BE615849, AA347837, AV750071, F34347, AI423886, BE008604, BF943546, H13879, BF760832, AW673014, H44340, BG057969, AW517794, AA326083, W46632, AI202612, AI342718, AA243222, AW080737, AI421139, AA218676, BF512353, T46960, AA613817, R62938, N27571, AI033297, AW290974, AI081667, W47438, T46961, R22209, AA515732, H53863, AI184234, BF871105, N80888, H53491, AA359923, R62937, BF987671, W20465, BF758781, AW340070, AW085155, BG002164, AW235210, AI086770, BE550493, BE905433, AA928979, AW440085, AA377667, AA844367, AI146951, W38558, H44339, AI682869, AA004374, R71722, AA366837, AW081995, AA226808, AI751146, AI733856, BG009211, BF805088, AA080904, R22263, BG222608, AW979191, BE315483, AW069227, AA833875, AA833896, AI634187, N57681, BF845136, AA315361, W32717, BG000735, AI923052, AI457313, AV762633, BG056362, AW805539, AU144540, AW265688, AU147162, AV695478, BE208115, AI890324, BE178489, BE245576, AA410788, AW970987, BE139139, AI250552, AW872736, AI284543, AA602906, AA441810, AA904211, AI884522, AW674631, BF965775, AI254770, AV759632, AW068596, AL524675, AI251284, BF916784, AI251034, AI251203, BF795891, AI583142, H73550, AW978041, AA916430, AW067788, BE138387, BG010084, AA669155, AW969667, AW963444, AI817230, T74524, AL020996.5, AL110205.1, AF166125.1, AC005052.2, AL034405.16, AC008403.6, AL049831.2, AL109804.41, AL359092.14, AC023490.5, AL024474.1, AF243527.1, AP000557.2, AC007664.12, AC007956.5, U91323.1, AL031295.1, U91326.1, AL133453.3, AC004150.8, AC010553.6, AL353807.18, AL034548.25, AL096840.25, AL121992.24, AC010679.6, AC026464.6, AC022088.5, AC068715.5, AC007292.1, AC002544.1, AC010149.8, AL138878.10, AL449363.12, AL138724.12, AC002316.1, AL121972.17, AF196972.1, AL354808.24, AL031602.14, AC008440.8, AC007536.9, AC008857.5, AL035587.5, AC022083.6, AE000658.1, AL050318.13, AC007193.1, AL121586.31, AC011464.5, AC008622.5, AC020904.6, AC005522.2, AC004983.2, AP001718.1, AC009131.6, AC008784.6, AC013355.7, AC004846.2, AC004699.1, AL355392.7, AL035407.15, AL391827.18, AC002472.6, AL136168.4, AC004089.25, AL034549.19, AC009144.5, AL031597.7, AC006251.3, AP000117.1, AC002301.1, AL031228.1, AC012634.7, Z82214.23, AC005751.1, AL355916.2, AL136979.16, AC016596.5, AC019205.4, AC005777.1, AL121890.34, AC004883.2, AC011450.4, AC002477.1, AL031311.1, AL008635.1, AL121897.32, AF001548.1, AF196969.1, AC037475.9, AC004854.2, AC004882.2, AP001705.1, AC011471.6, AC008064.2, AL049760.26, AC008755.6, AL035405.10, AC007011.1, AP000556.2, AC005399.19, AP000100.1, AP000261.1, AC068799.14, AL121774.5, AL137852.15, AL031283.26, AP000505.1, AP000088.1, AL033529.25, AC007308.13, AC006023.2, AC018719.4, AL136126.34, AL160269.14, AC006994.4, AC004020.1, AC005300.10, AL445649.15, AJ300188.1, U91321.1, AC009756.9, U53331.1, AC020913.6, AL137229.4, AC004263.1, AL445646.11, AC005209.1, AC005274.1, AL034420.16, AL022320.23, AC017004.4, AP001609.1, AP001610.1, U52111.2, AP000193.1, AC008895.7, AC004826.3, AC010530.7, AC000360.35, AP000035.1, AL033519.42, AC011484.4, AC005920.1, AL008732.1, AC017101.10, AC002347.1, AC005280.3, AL133289.9, AC011479.6, AL135838.5, AL353653.19, AC009996.7, AC004522.1, AL109811.39, AC018809.4, AL031662.26, AC008666.5, AC005519.3, AL136525.17, AC005736.1, AP001760.1, AC002551.1, AC012442.7, AC005484.2, AC011742.3, AC007917.15, AC004257.1, AL445205.14, AF134726.1, AC012320.6, AP001710.1, AC004686.1, AC004253.1, AC006328.5, AC012081.16, AP001719.1, AC004815.2, AC018764.6, AL353716.18, AL590762.1, AC004598.1, Z86090.10, AC011895.4, AC008891.7, AC024571.4, AC006115.1, AL109984.14, AC011521.3, AC005000.2, AL442167.1, AC011465.4, AC003990.1, AL136179.15, AC004801.1, AC007298.17, AP000510.2, AC009412.6, AC008569.6, AL035669.43, AL139415.10, AL021154.1, AC008736.6, AC007739.2, AP000553.1, AC005821.1, AL035079.14, AL1356805.5, AC008507.8, AC018758.2, AC007225.2, Z93023.1, AC004755.2, AC027130.5, AC025430.5, AL121936.17, AL161938.6, AL117336.22, AL133510.13, AC010148.13, AC006205.7, AC010582.6, AC022007.3, AL137792.11, AF288742.1, AC006966.3, AC010543.8, AL136040.5, AC011497.6, AC006285.11, AL049764.4, AC005071.2, AC024082.6, AP000963.2, AC006211.1, AC011462.4, AL450339.5, AC004847.3, AL021707.2, AC020558.4, AL031729.16, AL035089.21, AC010279.4, AL121594.6, AL117348.25, AC020916.7, AL136362.10, AL139022.4, N44105, AA243221, AA931615, AA218772, AA287130, AA394149, AA399173. HLHCS23 122 560663 1-1413 15-1427 AL512506.8. HLICE88 123 840321 1-826 15-840 AL532043, AI201573, AL531300, AL531634, AI989422, AL531496, AL531955, AI984220, AL531518, AI954841, AL531321, AF074698, AW339929, AL531471, AV651041, AA779747, AV651093, AV699907, AV650840, W72217, AI064748, AV654559, AV682392, AW269523, AV651109, AL531705, AV694886, AL531173, AL531868, AV654713, AV682656, AI174843, AV718993, AV690790, AV647604, AW665993, AI065032, AV700518, AI568934, AA936960, AV718549, AI092886, AI189826, AI187086, AV718380, AI911879, BE825390, BF126685, AV719205, AV650157, AI313492, AI917303, AV699400, T64315, AV682007, AV683969, AI186901, AW950039, AV662312, AA906009, AV658467, AI283155, AI580756, AI207724, AV700035, AL532119, AV682707, AI989903, AV682339, AI825233, AV718528, AV692690, AV661899, AV687963, AV649290, AV695138, R00044, AW074348, AV662232, AV662173, W68580, W77961, AV661196, W78129, W94563, AA312959, AV719960, C20909, AV655180, AA313014, AV647336, N79517, T53800, AV697776, W92647, AI140948, AV661818, AV653519, AV682459, T69024, T64703, R85625, AV659219, AV654902, AV654163, AV656147, AA343530, T62908, AV662293, AV646927, AV660491, AV661947, T27841, D12274, AV649738, AV719990, AL531635, W78014, T50716, AA344654, AV690645, AA343475, AV655633, AV694901, AV661905, AV653213, AV656799, T64666, BE250740, AV646035, BF884848, H89646, BF907679, AV684695, AV697617, T74885, AI266531, AV693375, BF700475, AV649852, AA312904, BF884387, T72273, AA360373, AA345098, T46873, AV649783, T40932, T64651, BF223298, BE971381, T73291, AA345478, T68149, AA344540, AV652797, T69397, BE786550, AA127901, T70574, H49804, T67493, AA313214, AV659816, W79416, AV648902, AA345122, AI808530, AV655148, BF059586, AV718825, T52365, T23996, T74611, AA313496, T69582, T68003, AV648713, T64115, AA345475, BF695457, AV682967, R09360, T69277, AA345347, AV662313, AA328409, AA780302, AA344998, T50690, T68193, T58776, AA313189, T50709, T74553, AA345561, AA345467, AV653080, T94279, BE693289, T69653, AI065018, BF126654, BE693283, T69258, T41064, AV688374, AV655766, BF814637, AA313124, AA331360, AA345116, AA360365, T73437, T67507, AA313165, AA345423, AV684262, AA382681, AA344388, T82069, AA345257, AV661807, AA313286, AA345507, T41037, AA313498, BF696362, AV692145, AA345440, T55851, AA345466, AA337510, AV681621, T83205, T55856, T72290, AW805833, AV655197, BE971173, AV659822, T58721, AL531497, AA344638, AA331364, AV656556, AL532136, BC007044.1, AF350254.1, M10014.1, K02569.1, X14174.1, X51473.1, X00086.1, T58742, T58809, T61213, T61761, T41027, T72141, T73555, T90758, R09244, R01860, R06531, H89500, W68581. HLQAS12 124 886180 1-2436 15-2450 AI928113, BF982378, AI357634, AI765282, AI453115, BG231939, AU157262, AV708295, AV727507, AW082681, BE501554, AI188985, AI095135, AU156104, AV726829, AU135631, N51624, AW440717, AU156188, AI244310, BF934257, AU137679, AU135523, AU138854, AI300045, BF917907, AA044216, BF914890, AA938683, AI868392, N75085, R78358, AA044087, R31345, H68138, R78357, AI419044, R62557, H67054, BF858325, AA620341, R26153, AI243883, R23598, R31604, AW969916, AA528481, BF110458, BE174919, R07930, AA682386, AA114093, N53919, AW298577, BF895809, AW796811, AB017444.1, AF079167.1, AB010710.1, AF035776.1, AJ131757.1, AF079166.1, AB017441.1, AF079165.1, AB017440.1. HLYAR30 125 781249 1-840 15-854 AW138760, AI928443, AI264363, AA428526, BG236171, BF432779, AA581388, AA854958, AI366182, BF446513, AW170385, AI970247, AI354301, AI081061, AI140964, AW243493, AW104079, AI366181, AA732881, AI039682, AA425694, H11979, R46377, AI871576, AI082699, AI767870, AW207325, H72841, AI537179, BE796247, N35990, AW168999, AI678150, AW972093, AA405499, AI191091, Z39960, AA626013, AW139286, AI283218, F03140, AA890408, N95266, AI871195, AI349325, BE791253, AI914847, AW088879, AA192077, AW090285, AA788656, BE674514, AI634559, BE797083, AI269823, AA894693, AW151974, AW151132, BG167830, AI431238, BE883591, AI537677, AI494201, BF812963, AI804505, AI815239, AI500659, AI866465, AI815232, AI866691, AI801325, AI500523, BF812438, AI538850, BE885490, AI358271, AI582910, AI887775, AI582932, AI872423, AI590043, AI284517, AI923989, AI500706, AI445237, AI491776, AI289791, BF811804, AI926593, AW151138, AI521560, AI889189, AI500662, AI285417, AW172723, AI539800, AI284509, AI582912, AI538885, AI440263, AI889168, AI927233, AI866573, AI633493, AI434256, AI355008, AI866469, AI805769, AI434242, AI888661, AI500714, AI284513, AI888118, AI285439, AI859991, AI436429, AI889147, AI623736, AI355779, AI581033, AI371228, AI431307, AI491710, AI440252, AI440238, AL047422, AI567971, AI866786, AI610557, AI860003, AI431316, AI242736, AI539260, AI828574, AI887499, AI440260, AW151979, AI539781, AI702065, AI539707, AI885949, AI285419, AW089557, AI559957, AI521571, AI469775, AI282249, AI866581, AW074057, AL047398, AI567953, AI815150, AI446495, AI867068, AI952433, AI225248, AI698352, AI371229, AL042750, BE891834, AW194509, AI866458, AI432644, AI890907, BF811802, AW129310, BF815930, BE897632, AI273179, AI371251, AI866510, BF814072, AI623302, AW058275, AI866461, AI923046, AI049859, AI539771, AL048403, BF525578, AA878808, AI890472, AI801286, AL515347, AI348870, AI889191, AI564500, AW151136, AW858522, BG252929, AL514281, AW858243, AL514033, BE895765, AI554821, AI561170, AI354981, AI690946, AI648567, BE877142, AI433257, AW191003, BE881384, AI500683, BE908336, AI815233, BG029667, BG030548, AL048375, AL514839, BG113493, BG260144, BG110517, AI355126, AI371243, AI687614, AW059828, BE963035, AL514427, BG257535, AI798359, AL039390, BF795712, AI493559, BF796402, BG163646, AI274759, AL045626, BF814447, BF342261, AI433976, BG254745, BE875243, BF726204, AI924051, AL136781.1, AL136644.1, AL359620.1, AL133084.1, AL133076.1, AL133070.1, AL136765.1, AL357195.1, AL133608.1, AL049423.1, AL136763.1, AL031346.8, AL136844.1, AL137547.1, AL110269.1, X98834.1, AL353999.3, BC001166.1, BC006440.1, AL122101.1, AL136825.1, AL133049.1, AL133655.1, S77771.1, AL353802.14, AC009484.3, AK026647.1, AF205073.1, BC006133.1, BC007920.1, BC008063.1, AL133053.1, AL133015.1, AF038440.1, AK027102.1, AL359622.1, AB012256.1, BC001774.1, D44497.1, AB047609.1, AC007869.2, X66417.1, AL157480.1, AF028823.2, AL137478.1, AF013249.1, AL122049.1, BC007926.1, AB048921.1, AL162062.1, AL136768.1, U51587.1, BC003602.1, U77594.1, AC012312.8, BC009192.1, AL137463.1, L19437.2, AK026746.1, BC000090.1, AF061795.1, AF151685.1, U72621.3, AJ296345.1, AC008491.6, AC007458.13, BC002750.1, AF271350.1, AF022813.1, AF038847.1, AB049900.1, AK024974.1, BC002448.1, BC002356.1, AF004162.1, U80742.1, X79204.1, AL357773.15, AL441883.11, AL442643.2, AC026464.6, AC004213.1, BC000051.1, AK027311.1, AL391244.11, AC002464.1, AK026626.1, BC000377.1, AK000212.1, AC004686.1, BC000007.1, AF111112.1, AL049465.1, AF131773.1, BC001236.1, BC006091.1, AK026480.1, BC002373.1, AL133640.1, AB060832.1, AB060874.1, AB063040.1, AB049758.1, BC004119.1, AL137555.1, AC007114.7, AC015982.9, BC005070.1, AK027614.1, AB049892.1, BC004529.1, AB049629.1, U67813.1, AL122050.1, AK027095.1, BC002485.1. HLYDF73 126 566869 1-612 15-626 AC009753.5. HLYDO73 127 584787 1-844 15-858 HLYGY91 128 658703 1-626 15-640 AW294783, BE502344, BE222441, AI082255, AI031661, AI701563, BF431032, AW340159, AI250886, AA164268, AA113365, AW195764, AA813476, AI382168, AW044458, AI802164, AI149406, BF196258, AU155794, AA479123, AI167291, AI436306, AI224847, AI417116, AI709346, AI669258, AW772002, AA844518, AI282711, AI279738, AW195230, AW959069, BF002627, AI560087, AI286319, AI474555, AI092394, AA479124, AA243709, AI468637, AW991244, AA508073, AA243826, AI468739, T62160, AW975954, T61934, BE707630, BE169617, BF747189, BE832694, AA746981, AA328991, AK023448.1. HMDAB29 129 584789 1-1176 15-1190 AV756491, AA714011, T74524, AW970571, AI284543, AA847499, H07953, BE139139, AI250552, BE676912, AI251284, AI251034, AI251203, AL042373, AI254770, BG169404, AW504485, AI223626, BE062159, AI755214, AW303098, AW500684, AI754567, AI053398, AI792575, AI754105, AI278972, AW576251, BE138594, BE138387, AW023111, BE315483, AI923052, AA449997, AW973992, AV762354, AW969667, AA829036, AA937809, BF725844, BE150796, BF832074, AW973757, BE968744, AI254779, AA773463, AI085242, AL119247, AI962030, AV763550, AW467607, BE674881, AV649707, AI674840, AA630854, AW167330, AV710482, AW265342, AV762975, AV649853, BE256101, AA315361, AW850517, AA828834, AW958962, AA828054, AI687343, AW963463, BG012020, BF854170, T11828, AW270771, AA621865, AI963720, AW502237, AV733437, AV723671, AA127426, AI732151, AL042667, AL042670, AI745151, AI249853, BE160727, AV762633, AW965008, AL119921, AI620992, AW969831, AA809546, BG110480, AA680243, AA618316, BG152386, BG115297, AW471332, BF950533, AI627614, AA524616, AA828637, AI524193, AW500161, AV763540, AV738383, AI613389, AI890971, AI279417, BG105498, BF724372, AL524675, AW970064, AA683069, AW265688, BF868994, AI049676, BG026977, AI457389, AW193265, AA503019, AI334248, AI440117, AA651639, AK025218.1, AC007308.13, AC002470.17, AC004824.3, AC010271.6, AL031283.26, AC009412.6, AC005399.19, AL136305.14, AC010913.9, AL135927.14, AC007227.3, AC011455.6, AC008670.4, AC016602.6, AC006337.4, AP001718.1, AL049839.3, AL033524.11, AC006038.2, AF200465.1, AC005200.1, AC005233.2, AL109804.41, AF051976.2, AC010319.7, AF243527.1, AF207550.1, AL121601.13, AC005077.5, AL133367.4, AC005740.1, AL117333.26, AC005324.1, AC004821.3, AC011895.4, AC007956.5, AL137849.13, AC006433.18, AC007991.7, AL139415.10, AC022211.5, AL024498.12, AL159997.14, AC011740.7, AL161731.20, AC016995.4, AC005529.7, AC004953.1, AC007722.9, AC006330.5, AC026464.6, AL359986.15, AL121895.26, AL031228.1, AL031276.1, AC006965.3, AC004134.1, AL050350.14, AC022148.5, AC004408.1, AC008755.6, AL050349.27, AL109806.22, AL133240.3, AP000963.2, AL034379.8, AL109843.25, AP001709.1, AJ277546.2, AL121972.17, AL031670.6, AP002852.3, AB038653.1, AF045555.1, AL031311.1, AC003080.1, AL020997.1, AL121808.4, AP000117.1, AC004796.2, AL354707.17, AC020552.4, AL122020.5, AC009131.6, AC008752.6, AL158817.11, AC009488.5, Z98884.11, Z83826.12, U63721.1, AL049776.3, U62292.1, AP000298.1, AC005484.2, AL132768.15, AL161747.5, AC018636.4, AL158207.15, AL137119.26, AC005409.1, AC012372.4, AL449209.2, AC008440.8, AC074013.5, AE006464.1, AC004813.2, AC009032.7, AC007676.19, AC018462.4, Z98304.1, AC011495.6, AL359092.14, AC008753.8, AC005527.3, AL034417.14, AL121753.30, AL033527.26, AL109921.21, AL132640.4, AC009068.10, Z85996.1, AL035684.25, AF317635.1, AP000424.3, AC000025.2, AC008521.5, AL158040.13, AC019171.4, AC006952.6, AC004024.2, AL031847.17, AJ011930.1, AC011479.6, AL163300.2, AL109976.23, AC004707.1, AC006121.1, AF053356.1, AL022316.2, AL121594.6, AL160165.17, AP000429.3, Z98946.15, AC005236.4, AC006064.9, AC010608.6, AL035411.27, AL365444.11, AL031428.9, AC010422.7, AC003682.1, AC005921.3, AL109801.13, AL354668.13, AL137139.9, AC005971.5, Z93017.6, AP002453.3, Z82215.1, AC008050.6, AL049694.9, AL022312.7, AC005071.2, AF196970.1, AL133163.2, AL451075.15, AC005086.2, AL035071.17, AC004156.1, AL136295.3, AF196779.1, AC022382.3, AL391280.15, AC020898.5, AC006057.5, AC004659.1, AC012614.6, AL121712.27, AL136137.15, AC005058.1, AP001711.1, AC005995.3, Z82206.1, AL139343.9, AP000925.5, AP000044.1, AP000112.1, D84401.1, AL096791.12, AP001781.4, AC004826.3, AL158052.10, AC005225.2, AC004975.2, AC004797.1, AC007546.5, AC083884.6, AL355517.12, AC011465.4, AL109935.39, AL132712.4, AL021808.1, AP000193.1, AC023798.16, AC005914.1, AC005229.1, AL158830.17, AC004253.1, AC005056.2, AL391259.15, AC008745.6, AC008760.6, AC072052.6, AC019195.10, AC005620.1, AP001670.1, AP001748.1, AC034200.6, AC004494.1, AC004883.2, AL121936.17, AC009086.5, AC004084.1, AC005907.1, AC003043.1, AL109936.10, AL357519.19, AC004832.3, AC007435.12, AP000501.1, U96629.1, AL137229.4, Z84469.1, AL132777.4, AC008895.7, Z83840.7, AC005274.1, AC005412.6, AC025262.27, AC008649.6, AL391833.10, AC009269.6, AC015651.18, AC011494.2, AL161665.5, AC005332.1, AC011737.10, AP000796.4, AC008687.4. HMDAD44 130 566854 1-1190 15-1204 BF574085, R12644. HMEDE24 131 837027 1-2822 15-2836 BE799690, BF971352, AL522117, BE741614, BE733821, BE253979, BE745589, BE747602, BE275209, BE740081, BE797620, BG176608, BE741557, BE745137, BE560375, BE746312, BE732858, BG025369, BG178395, BF791999, BG254540, BE791922, BG255293, BE397859, BE563260, BF568255, BE736997, BE869657, BE733788, BG179867, BE744696, BF568603, BG105384, BG164812, BE735863, BE877940, BE513940, BE730519, BG028893, BE545980, BG253222, BE902894, BG181129, BE383086, BF688245, BE271622, BG104781, BG119401, BE780014, BF569659, BE304608, BE514068, BE297300, BG032303, BE298208, BE514435, BE907329, AW854046, BE301884, AV697512, BG117108, BE279314, AV661771, BE251240, BE407499, BE258199, BE311769, AW732511, BE298556, BF037695, BE388413, AW732535, AW409655, BE397925, AV683853, AA452189, AW854101, BE279938, BG116638, AV683681, BE563147, BE388057, AW854252, BE311605, AV661878, BG122628, AW995622, AW361325, AV683485, AA503078, AA573738, AV702970, AA582834, AW853978, BE788746, BF037900, AW965408, AV685743, BE075197, BF203617, BE745948, BF854007, BE378390, AW068660, BE867357, AW068659, AA206520, BE271811, AW854032, W73087, BE908750, BE514234, AW965028, BF663829, BE560624, AA147831, BE269587, BE551372, BE388856, BE504255, AW368613, AA098841, BE696091, BF304862, BF313245, AW205582, AA083178, AA507028, BE296877, BE019783, W31114, BE877527, BF316131, AI140368, BE254196, AA129205, BF988424, BE873091, AV723475, AV694405, AA131227, BF982711, BF875737, W67728, AW361340, AA608672, AW379832, BF247344, BF316864, BF211638, W58606, BE075179, BF032794, BE261375, AW574704, AA102507, AV701713, AI085375, BE387881, W67729, AI026933, AA846817, W72755, AA101137, BE514707, BG107229, AA082572, BE868602, BF206336, BE696064, AW753393, AA522536, W73192, AI813745, AA928422, W60774, AI126196, AA587677, BE313256, BE208156, AI951015, BE263252, BE547308, AA599278, AI754718, AI857952, BF569994, AI687726, BF683745, AI199748, AA307277, BE931179, AW403826, AA131954, AA081036, BE019776, N20199, AW582700, AI817097, BE383366, BE671712, AW469365, AI129011, W48714, BF243582, AW137417, AA836853, AW377041, AA187427, BE252430, AA131867, W69472, AA181263, N77269, AA977798, AA515651, AW192685, AB045226, AW361334, AA728801, AA633355, AV696934, AW172760, AV698033, AV698614, AA477847, AI831569, AI304653, BE712847, AI921567, AW403885, AI819145, H66250, AA598702, AA442280, BE313723, AI079407, BE867804, AI074293, AI077702, AI472721, AA083479, BE514162, AW593751, AI292021, AA085537, AA262168, W24339, AW769027, AA505866, AK025006.1, AL133541.21, BC001199.1, T69870, T70201, T92335, T92384, T96386, T96472, R17622, R20030, R36294, R53689, R61494, R61495, H19159, H24545, R93422, R93473, H56339, H56338, H64262, H77895, H87909, H99002, N29100, N49461, N70625, N94352, N95465, N95500, N98726, N99983, W05507, W25205, W31007, W48715, W48678, W58607, W60488, W69339, W72030, W76275, W77954, W95403, W95452, N89750, AA005259, AA005260, AA022748, AA022850, AA033602, AA033601, AA058813, AA081037, AA082101, AA082395, AA083289, AA083408, AA122255, AA127457, AA127525, AA130470, AA130469, AA131210, AA136613, AA136745, AA147049, AA173175, AA182763, AA187330, AA187016, AA186912, AA188454, AA190352, AA262233, AA502579, AA503216, AA535682, AA536157, AA557268, AA594665, AA618316, AA576258, AA580400, AA857905, AA876095, AA915957, AA931703, AA961340, AA988937, AA991158, N56514, W17285, C00034, N86769, C16493. HMEDI90 132 840077 1-2262 15-2276 BF951698, AW956936, H29379, T66089, AA057405, AW134660, AA057093, AA917450, AL133995, AI299437, AI002692, H18042, R19493, T09261, F11783, F11794, T65008, T09262, R43839, N78357, H29290, AL035633.18, AF263308.1, AF263309.1, AF263310.1, AF263307.1, AF263306.1, AF263305.1. HMIBD93 133 634227 1-1309 15-1323 AL045780, AW590225, AW970178, AI376010, AI401550, BF940066, AW072377, AI362753, AW005335, AA524093, AW575918, AW592039, AI097125, AA514373, AI424874, AA490412, R55849, R89670, AA502607, AI361469, W60204, R45456, AA906578, BF940638, H17344, W35351, AA757050, D52329, AA309188, AA490314, AA479853, R45361, AI929199, AA456776, AA394201, AA806240, R55770, W32915, AI380329, Z38945, AI003744, AA411018, R52109, AI471415, AA863370, AW953330, AW866322, BF921092, AL048656, BF038804, AW238730, BF904194, BG180996, AW075305, N49165, BG117375, BF764538, BE966011, BF343568, BE536058, BG104775, BG104699, AI684013, BF344691, BG121999, BF822127, BE966787, AV759922, BF969316, BF904258, BE393551, AI498067, BE965121, BF753053, AL039086, BE895765, BE886728, AV721967, AI923989, BE254907, AW004896, AI648699, AI872914, AI312428, BF798503, BE895585, AI636619, AI620056, AW059828, BF812459, AW162189, BF835240, BE875243, AW411235, BF885000, AL138406, AI887775, AW071417, AI961589, AI307557, AI611728, BE964876, BE047833, BE966699, AV704051, AI950892, AI620639, AW827289, BF339322, AI917963, AI810589, AI345677, BF792928, AI824375, AI537677, AW410972, AL040277, AW084056, AW834302, AL040241, AI538885, AW151136, AI270055, AI570966, AL040694, AI446373, AI916419, BF856052, AI473451, BG110517, BF854113, AW149876, BF204484, AA420758, AL036652, AI571511, AW411043, BG151388, AI288285, AW409775, BE965724, AI002285, BE891101, AW410969, BE907440, AI866770, AL043052, AW827115, AA572758, BE543089, AL119836, AI955906, BF753013, AI889376, BE892572, AI468872, AW409931, AI340519, BF960601, BG029053, AW858254, AI307734, BF672397, AI521103, AL036780, BF818009, BF817392, AI590686, AA493647, AI929108, AA853213, AI922901, BE878725, AA420722, AI432653, AW167918, AW999049, BE965192, BE544111, BE963838, BG105895, BE964614, AI570909, BG107576, AI378123, AI623941, AI874243, D50977, BE963286, AI440263, AW088899, BE963918, BE072233, AW858243, AI366549, AI636719, AI539153, AL040011, BF813196, AI269909, BE964767, BF904180, AI539771, BE962636, AI524608, AI349933, BE045182, BE964700, AI866608, AI611743, AI249877, BF990167, AW083804, AI590423, AI783504, BF829164, AI580190, AI696626, AW089006, AI345253, AW935969, AI589993, AW059713, AI365256, BF909758, BF853807, AV656595, BF337602, BE964497, AW411351, AI567582, AL037582, BF816037, AL037602, AI564719, BE538466, BF816811, BF814761, BF885082, AI249962, BE965432, AL138457, BE904911, AI581033, AV698087, AW090494, BE965758, BE620444, BE613727, AC010913.9, AL136884.1, BC003602.1, AL133016.1, AK024538.1, AL117432.1, AL133558.1, BC005678.1, AB044547.1, U42766.1, BC004960.1, AL110197.1, AK026528.1, AL122098.1, AF218031.1, AB048975.1, AL162002.1, AK027868.1, BC003410.1, BC007456.1, AK025092.1, AB046642.1, BC004196.1, BC004899.1, AK025339.1, AK025798.1, AL137281.1, AL133075.1, AL137656.1, AB051158.1, BC008364.1, AL137538.1, AL512718.1, AF217982.1, AK000647.1, AL137550.1, BC005890.1, AK026494.1, Z37987.1, AB055368.1, AL136768.1, AL157431.1, AL110280.1, AB062750.1, BC003687.1, AF003737.1, AB060929.1, AF348209.1, AK025015.1, AK026629.1, AL353625.5, Z82022.1, L30117.1, AB047904.1, AL389982.1, AK027111.1, AL080060.1, AL162083.1, AK027096.1, AL049283.1, AL512719.1, AK000432.1, AF069506.1, AL050280.1, BC007926.1, AB062978.1, AF162270.1, AK026534.1, AF028823.2, BC001774.1, AL359583.1, AK024974.1, AB063084.1, AL049452.1, AB063079.1, AB060852.1, BC004244.1, AL110228.1, AF146568.1, BC007346.1, BC000778.1, BC005151.1, AK026533.1, AK027081.1, AL080074.1, AK000391.1, AK026462.1, BC008780.1, AF090943.1, AF218004.1, AB055374.1, AK027213.1, U91329.1, AL389935.1, AB049892.1, BC001418.2, AF026816.2, AL122110.1, AL359941.1, AL137283.1, AK025391.1, AL136640.1, AF217966.1, BC008284.1, AB060908.1, AF217987.1, AK025407.1, AB060916.1, AK000212.1, AK026855.1, AL137529.1, BC001098.1, AL136747.1, BC004556.1, AK026551.1, AY026527.1, AL117435.1, AL136787.1, AL136882.1, AL136805.1, BC006195.1, X98834.1, AK026408.1, AB055361.1, AK024594.1, AL136692.1, BC004529.1, AL050024.1, AL049430.1, AL133640.1, BC008280.1, AF177228.1, AF183393.1, BC000090.1, AB052191.1, AL080127.1, AF090886.1, AF056191.1, AL050138.1, AL137479.1, AB060912.1, AL512684.1, BC006164.1, AK027200.1, BC000317.1, AK000323.1, AL136864.1, AL080126.1, BC003122.1, AK026624.1, X72889.1, BC001470.1, AB048953.1, AF111112.1, AL050393.1, BC003052.1, AL137556.1, BC002839.1, AK026583.1, AL136786.1, BC002519.1, AK026630.1, AK026526.1, BC007198.1, BC004191.1, AK025383.1, AK026592.1, BC008365.1, AC044797.5, AL389939.1, AK027116.1, AK024524.1, BC002457.1, BC003627.1, AB048994.1, AK026353.1, AL122050.1, AB055370.1, AL512754.1, AK025209.1, AL389957.1, BC008485.1, AB056809.1, AL080162.1, AF090903.1, S77771.1, AJ012755.1, AL136749.1, BC007021.1, BC009341.1, AL137463.1, AK026542.1, AF090934.1, AL137526.1, AL136767.1, AL049382.1, AL117583.1, AL512733.1, BC004195.1, AB056420.1, AK027204.1, AK025431.1, AL117585.1, AK027160.1, AK000291.1, AL359601.1, BC007998.1, BC007534.1, AF352728.1, AL080148.1, BC001206.1, AL133565.1, AL133112.1, AK000486.1, AK026532.1, BC004923.1, BC008387.1, BC002539.1, AL110196.1, BC008899.1, AK026642.1, BC004265.1, AB060837.1, BC003110.1, AL133081.1, AK026959.1, AL136915.1, BC003548.1, BC008417.1, AL353935.1, BC006412.1, AK026506.1, X53587.1, S78214.1, AK026608.1, S61953.1, AF078844.1, AF100781.1, AF358829.1, AF097996.1, AL133093.1, BC006509.1, AK025967.1, AK026480.1, AB063070.1, AK024545.1, BC002643.1, AF218014.1, AL390154.1, D89079.1. HMIBF07 134 603528 1-1724 15-1738 HMJAK70 135 610099 1-785 15-799 HMQAI38 136 589964 1-1763 15-1777 HMSHY25 137 886183 1-2191 15-2205 BF822591, U63312.1. HMUAN45 138 833072 1-2695 15-2709 BF975230, BG177292, BF683936, BF972280, AW452044, AW450817, AW571669, AW276243, AI223336, BF507478, AW953367, AI937821, AA354094, H45305, AI699989, AI624920, AA251791, D19672, AA922638, AI655588, AA928313, R74251, AA339800, H45245, BG056723, AI433894, AW080419, AI023763, AI040104, AI523987, AV681951, AI611728, AA769327, AI564716, N22276, AV761484, BG108350, BE672647, AW268067, AL513781, AI924035, AI925463, AI811192, AI613144, AL037558, AV688427, AW083111, AI963101, AA825509, AV734888, AW955613, AL135022, AW020693, AA437293, AW197174, AI910902, AI954468, AA584251, AA420722, AW963250, AI318569, C21335, AA292158, AI742728, AV692108, AI311892, BE906230, AK027899.1, BC001812.1, AB046039.1, U42766.1, AL133016.1, AF069506.1, BC007548.1, AK025761.1, BC002643.1, AB049892.1, BC008893.1, BC002697.1, BC007199.1, AL133568.1, AK026603.1, AF218004.1, BC002736.1, AF227198.1, Z48796.1, AK000205.1, BC004383.1, AL133557.1, X79204.1, BC004529.1, BC001817.1, BC008285.1, AF090900.1, AL035067.2, BC006487.1, AL353957.1, AL137281.1, AK024978.1, BC008796.1, AL136321.5, AB009690.1, AK025860.1, BC007674.1, U31501.1, BC002839.1, AB060842.1, AF094480.1, AL136781.1, S71381.1, AB060229.1, AB060927.1, AF218014.1, BC000749.1, BC001829.1, AK025798.1, AL133113.1, AJ238617.1, AF044221.1, AK026494.1. HMVBC31 139 825598 1-2542 15-2556 AL513958, AL532289, AL513957, AU141081, BE740204, BG166399, BE904675, BE891108, BG256305, BE744952, BE905626, BE742828, BE899088, BE745625, AV653746, BE866918, BF982216, AW957312, AV723081, AI819405, BE281510, BE514995, BE856665, AI818085, AW612700, AW963890, BF038873, AW005883, BF111236, N31954, AI570554, AI814284, AI743921, AI373828, AW963892, BF001263, AI073849, AW978642, AA705064, BE858940, AI078328, AI831014, AW963886, AW081533, AW953584, AA150396, BE906561, W78108, AA934651, W79933, D53129, N92092, AI669184, W03272, AA594574, AA719546, AA688147, AI042436, H47299, AI304898, BG012798, R35487, AA724939, W46177, BG012794, AA661822, W46540, AA158922, AI968456, R44002, AW277188, AA352968, T75515, AW365085, BE278604, AI754560, BE817848, R94999, H60086, H59434, AI868335, N69447, F19605, AA156578, D54824, AA903411, AA449263, Z24956, AW857481, BE073224, BE466451, AW857479, AI468314, T33942, H47300, Z46090, T30256, R41822, F03578, Z40826, N36752, BG149926, R94915, AA993003, R32790, AA577458, AW594657, Z44501, AI383141, AA449397, D80727, AA365266, BF757856, AA040902, AA768178, AA768128, AI391494, AA814775, BE140388, BG035024, AI814155, AI940059, BF435821, BF435237, R34285, AW300688, AA984028, BE140425, N34605, BF448850, AW169682, AW805217, BF855415, AW751033, BE934304, AA627953, AW834022, R32791, N55681, BE172132, AW751067, AA143108, BE019916, BF759114, T19783, AW835471, AL031847.17, AF064084.1, AL117548.1. HMWBL03 140 822861 1-2582 15-2596 AL532317, AW976696, BG258766, BE784103, BE781381, BG115099, BF215477, BG163228, BE868152, BG119548, BG118210, AW978736, BE547477, AI992158, BF103579, AW394038, BE537694, AW835469, BG256663, AW070824, BE614387, BF031478, AW157294, AI743202, AI193598, BF029929, BE538143, AW303817, BE464933, AA939106, AW835466, BE869327, AW835470, BE966420, AW394036, AI831483, AW163057, AI979181, AA306435, BE613678, AA749314, AI094155, AW157089, AW362974, BF240145, BF217794, AW731659, AI878985, AW362965, BF795374, AW956998, BF217096, AA146858, BE568486, AW162479, AA648921, AW753912, AW362949, AA311937, AA908739, AI922877, AI879487, N51950, AA406456, AW362962, BE350612, AI346620, AA306611, BG055455, AA651863, AA775633, AA768709, AW614887, AA774684, AA284818, AA813993, AW362967, AW769884, AA581615, AA146857, AI378205, AW362950, AI382916, AW362951, AW403413, AA586521, AW407973, AI674283, H59390, AW362956, BF913578, BF914518, AW169393, BF914514, AI473650, BF914275, AA406348, BF916334, BF913574, AA379531, BF108888, AW610254, AI225213, AA377822, BF095168, H60046, AA372701, AA465473, BF210038, AA310305, AA360185, BF914123, AA332342, AA120901, D81998, W21240, AA331393, AI382409, R18124, BE697930, AA736861, AI351496, AW752542, AA312498, AA971457, AI223218, AA377328, AW964009, AA096093, AW673672, AA300637, BF915447, T24898, AW163350, AA248513, AW389592, N95719, N53714, AW854099, AW366952, AI690275, AA492352, AA745999, AW975618, AW960465, AV718692, AW973445, AW966534, AV718931, AW973541, C14331, AW966330, D50979, AV718489, AW964468, AW966059, D51423, AV720533, AW949645, AV699866, AW959136, AW973474, AV720791, AV719324, AW965175, AV720731, AW966398, AW973307, AV718707, AW966386, AV719557, AV720616, AW966331, AW978661, AW949654, AV724520, AW959202, D80248, D80166, AW978634, AW966369, AW973490, AW966389, AW960473, AW959799, D80188, C14389, D59859, AW975613, D59619, D80210, D51799, AV720151, AW960553, D80240, AW958992, D80253, AV719822, AV718938, AV718633, AW975605, AW966378, AA305409, AW966053, AW973488, AV720211, AV720878, AW966368, AW966029, AV699447, AW966397, AW958993, AV722801, AV723927, AW949656, AW949642, AW966399, AW966531, D81030, AW966075, AW966065, D58283, AV744690, AW973334, AW966333, AV720203, AW973447, D80212, D80366, AW966022, AV718440, AV720028, D51060, AV699550, AW965185, AW965197, AV718770, AW966013, AW973482, D80022, D80219, AW956397, AW956434, AW966041, D80043, AK027642.1, AY029179.1, AK027628.1, AL021808.1, AB028859.1, AF058696.1, AB002449.1, AF271371.1, X67155.2, D34614.1, D88547.1, D50010.1, AB038216.1. HMWCG28 141 847413 1-879 15-893 AW197242, AA115972, AA283140, AI768512, AI262126, AW299591, BE501477, AI492452, AI470922, AI925912, AI479591, H99611, AW392956, N53011, H58193, BF930214, H89604, AW361279, N34132, AW865961, BF933761, BE252200, BE083984, N35841, AF061944.1, AJ296290.1, AC004765.2. HNECW49 142 639117 1-475 15-489 AL162497.20. HNFCY57 143 877653 1-2833 15-2847 AV741792, R94860, AW468866, AW176538, R94861, C01539, AW793380, AI954796, AI819545, AI583966, AI590630, AI147877, AI812091, AI274484, AA814517, AI783997, AI950729, AI637584, AI376425, AI866458, AW198090, AI696714, AL514455, BG001315, AL514469, AI473536, AL514015, AI364167, AI469262, BG254286, AW152621, AI885664, AI972497, BF724894, BF724284, AL513977, AI126920, AI421222, BF868489, BF752870, AI633125, AI469425, AW152182, AI279925, BF970652, BF669151, AI864102, AI701097, AI915291, AI432644, AI538564, BG179993, AI633317, BF811804, BF753014, AW088717, BF752997, AI828239, BG122005, AW105296, AI499570, AI174799, AI266643, AK027194.1, AL080163.1, AB047878.1, AF090934.1, AL389935.1, AK027173.1, AL117587.1, AL110223.1, Y14314.1, AL080139.1, BC006463.1, AK025435.1, BC008037.1, AL389947.1, AK026593.1, BC004945.1, AL122116.1, AB055331.1, Y13350.1, AK027172.1, AF124728.1, AJ299431.1, AL137533.1, BC004264.1, AK000414.1. HNFGR08 144 825417 1-1422 15-1436 AC006369.3. HNGAK51 145 603910 1-901 15-915 AV731286, AW085751, BE156019, BF826830, BE067011, AI732911, BG260565, AV763498, BF747038, AV759172, BF816106, AA493475, AW405593, BE300645, AI457389, AV691908, AV696428, AV684596, AV695357, AV760383, F08248, AV730391, BF673743, BE063437, AI832009, AA583394, AW150209, AA515728, AA984258, AW575171, AV738383, H07953, BE150580, AV762783, BF681619, AA176972, BE748332, AW303196, AL035703.20, AL133445.4, AC024561.4, AC012039.10, AC010583.5, AC005844.7, AC026400.3, AC006477.3, AC022493.12, AC007000.2, AC005803.1, AC007207.22, AL138849.12, AC007097.4, AC068130.3, AL049650.8, AC006059.3, AC006334.3, AC008012.8, AC001231.2, AC009955.4, AL133409.14, AL133244.1, AC010585.6, AL121989.12, AL110502.1, AL133463.16, AC011740.7, AL513008.14, AL022147.3, AC011900.6, AC012150.16, AL109759.4, AC090527.3, AC090947.1, AC027126.4, AC004386.1, AC004814.2, AP001667.1, AL121578.1, AL157791.4, AL132639.4, AL031274.1, AL139109.14, AL499582.13, AC078841.4, AC073964.3, AC005939.1, AC022073.13, AC012170.6, AP001660.1, AC090946.1, AC002288.1, AL035604.15, Z83843.1, AB000882.1, AL049870.3, AF238375.2, AC005274.1, AL139322.13, AC008280.4, AC026172.3, AL078646.29, AC004887.2, AC019212.4, AC000029.17, AL359644.10, AL451103.7, L11910.1, AL009051.1, AP001666.1, AC002418.1, AC022443.4, AL139382.12, AL354760.11, AL158832.13, AC009194.8, AC009102.9, AL008710.1, AC005901.1, AC004859.2, AL157886.11, AC019205.4, AF205588.1, AL353764.9, AL391415.12, AC019097.5, AC004600.2, AL162551.3, AC025097.41, AF198097.1, AC016776.6, AP000122.1, AF265340.1, AL139193.4, AC010205.5, AC008784.6, AL136303.15, AC012312.8, AL360270.18, AC021752.5, AL136980.5, AP000751.4, AC012450.9, AC005409.1, AC008733.7, AC084782.2, AL096791.12, AC079127.28, AC007345.5, AC007671.7, AC009455.8, AL392048.9, AC024247.4, AC016770.10, AP000506.1, AC026310.24, AC010223.5, AL022165.1, AC021851.4, AC016748.3, AC003029.2, AC020898.5, AC007374.6, AL358612.8, AL133383.10, AC008066.4, AL359636.17, AC007637.9, AP000054.1, AC034145.5, AC004701.1, AF224669.1, AC073366.3, AP001680.1, AC004067.1, AL353692.14, AP001716.1, AC015592.6, AL359397.3, AL132774.20, AL160281.17, AC009996.7, AL157713.10, AC000113.1, AL031432.1, AL391827.18, AC025962.5, AL117337.25, AL136231.12, AP001677.1, AC004934.1, AL049589.15, AL136123.19, AC069282.6, AC009961.11, AL512307.12, AC005076.2, AC004458.1, AC016948.4, AP001727.1, AL163213.2, Z68870.1, AP001720.1, AC000120.1, AL389889.11, AC010369.6, AC010679.6, AC002128.1, AC007543.4, AL391139.19, AC090710.16, AL049830.3, AL137191.5, AL035530.11, AC011242.8, AL389888.8, AC007558.3, AL021397.1, AP003697.1, AL161415.2, AC004998.2, AC004741.1, AC007963.7, AC087857.2, AC019100.4, AL354937.12, AC068724.7, AP001671.1, AL035587.5, AL109804.41, AC073332.13, AP000350.1, AL358372.11, AP001329.3, AP001717.1, AC019206.4, AL356244.12, Z84480.1, Z93020.1, AL157955.5, AL096793.20, AC005725.1, AC025159.28, AL357507.9, AC005926.1, AC008462.6, AC022201.4, AC004478.1, AC022459.6, AL450342.14, AL590762.1, AL354861.11, AL138783.6, AC017006.4, AP002008.5, AL031963.40, AC084373.24, AC006160.9, AL031123.14, AL137787.11, AC090017.18, AP000053.1, AP000168.1, AP000121.1, AC004216.1, AL357150.7. HNGDX18 146 1145071 1-1411 15-1425 HNGFR54 147 695748 1-481 15-495 AC007316.4. HNGGA68 148 638116 1-571 15-585 AB052201.1, AJ236595.1. HNGHK37 149 609889 1-1529 15-1543 HNGIV64 150 561572 1-1033 15-1047 AA595803, AV653403, AI886084, AV684943, AV695480, AI363970, BF848469, AW380640, AV651029, AL049541.24, AC009475.4, AC020910.5, AC008556.5, AC067941.7, AC004967.3. HNGJB41 151 852178 1-1232 15-1246 BE256247, AF288742.1, AC004542.1, AF323731.1, AB051451.1, AF288741.1. HNGKT41 152 836061 1-1034 15-1048 AW862214, AW859811, AW862215. HNGMW45 153 838613 1-1516 15-1530 HNGNO53 154 836063 1-811 15-825 R37935. HNGPJ25 155 834942 1-839 15-853 HNHCT47 156 634691 1-607 15-621 AA469441, AA328289, AW972888, AW968156, AA502813, T09124, AI821722, AI732162, AI821172, AI792063, BE146613, BE146622, AU119400, AU119141, AA736713, AA572983, AL120694, BE392609, BF676104, AA598663, AI798242, BF346320, AA525409, AA834799, AW970987, AA525174, BE747883, AI636734, BF129921, BE395693, BF869362, BE677425, BF345228, BF345114, AA502536, BF747666, AA569179, AA482323, BE537881, BF871505, AV695478, BF340209, AI824589, AI567106, AV719084, AV763603, AA364869, AL079869, AA608741, AA468456, AA652059, AI309943, AL046620, AL041895, AA621838, AL031728.12, AC018828.3, AC022383.3, Z84480.1, AC011737.10, AL135839.15, AC083884.6, AC025594.5, Z83844.5, AC002470.17, AC007308.13, AL513008.14, AC009228.4, AC007597.3, AC006388.3, AL096841.6, AF109907.1, AL021546.1, AL133448.4, AC005098.2, AC004694.1, AC011461.4, AL133245.2, AC004815.2, AC004166.12, AC009488.5, AC004846.2, AL161756.6, AC009137.6, AC004030.1, AL157823.9, AL031685.18, AC015801.25, AC002369.1, AC020931.5, AC022384.4, AC010463.6, AC005803.1, AC018712.5, AC008569.6, AL035704.9, AL118502.38, AL049760.26, AC010378.6, AL353193.7, AC008755.6, AL138759.20, AC000360.35, AC007883.3, AC034193.4, AC007057.3, AC009475.4, AL049872.3, Z84486.1, AC005089.2, Z93020.1, AC011490.7, AC005871.3, AC009077.7, AC018808.4, AC007384.3, AC008745.6, AL132768.15, AL590762.1, AC008481.7, AC020954.6, AC010316.6, AC004967.3, AL356257.14, AC005972.1, AL096774.9, L44140.1, AC005052.2, AF031078.1, AL121586.31, AL391384.18, AL353748.13, AL133371.3, AC005081.3, AF030876.1, AC004073.1, AC011736.4, AC005067.2, AL159168.15, AL121920.21, AC013717.8, AL365364.19, AL022476.2, Z97184.1, AC004887.2, AL161670.4, AP001781.4, AC010319.7, AC002126.1, Z93015.9, AC009060.7, AL391827.18, AC026765.22, AC016027.15, AC007685.2, AC012170.6, AC008655.6, AL031651.33, AC016830.5, AC008551.5, AC005080.2, AC008040.7, AC004965.2, AC008521.5, AC011446.6, AP002007.4, AL133294.10, AL356915.19, AL157951.5, AC004760.1, AL121890.34, AL355871.5, AL136170.12, AC007917.15, AF053356.1, AL031681.16, AC011465.4, AC010999.6, AC084864.2, AL049576.19, AL132775.29, AP001760.1, AC004685.1, AP001725.1, Z75407.2, AC003070.1, AL354864.16, AC007881.4, AP000424.3, AC010271.6, AC010742.4, AL162430.15, AP002340.3, AL079342.17, AP000553.1, AC005841.3, AL096700.14, AC011495.6, AL137853.12, AC004799.1, AC025588.1, AC008267.6, AC011462.4, AC005914.1, AC087071.2, AC022154.3, AL139415.10, AC003043.1, AL121926.24, AC004491.1, AC011005.7, AL117381.32, AC026805.5, U91323.1, AL034422.24, AP003466.2, AL049709.18, Z68273.1, AL359092.14, AC005207.1, Z93930.10, AC008266.3, AC004382.1, AC007388.3, AC009131.6, AL136981.22, AC005082.3, AL122023.3, AC083855.2, AL117350.12, AC018801.4, AL136305.14, AC010328.4, AL049761.11, AC000025.2, AC010422.7, AC078818.19, AC026866.8, AC011811.42, AC007842.1, AC005200.1, AL355392.7, AC008389.4, AC004883.2, AL139801.17, AC011460.3, AL160264.22, AC020552.4, AC011472.7, U47924.1, AC018751.30, AB013139.1, AC007318.4, Z83838.2, AL121897.32, AL133153.3, AP001753.1, AL096840.25, Z93017.6, AP000349.1, AC011247.10, AL049869.6, AC004782.1, AC090527.3, AC006088.1, AC020928.6, AD000812.1, AC011479.6, AL022721.1, AC018695.6, AC002430.1, AL139100.9, AC004854.2, AL132712.4, AL139002.18, AL162426.20, AL161445.10, AC007546.5, AC000026.3, AL109797.18, AC020983.7, AC020913.6, X69907.1, AC005620.1, AP000350.1, AC010205.5, AF224669.1, AC058791.3 AP000352.2, AF011920.1, AC004703.1, AC018711.4, AC008623.4, AC006946.20, AL035689.26, AC007383.4, AJ400877.1, AC004953.1, AL035420.15, AC023880.5, AL159140.4, AD001527.1, AC002394.1, AL035072.16. HNHKI74 157 777856 1-803 15-817 AV728309, AV707794, AV706891, AV725423, AV704740, AV709273, AV702172, AV701844, AV734690, AV683012, AV705525, AV734974, AV703460, AV702625, AV702760, AV705299, AV732961, AV726754, AV702857, AV706410, AV728425, AV764444, AV704467, AV762687, AV759295, AV725431, AV707135, AV762870, AV727065, AV702659, AV759719, AV759507, AV762973, AV761810, AV706448, AV760057, AV761107, AV729881, AV759717, AV761489, AV761613, AV729947, AV707230, AV762505, AV722143, AV755512, AV763558, AV763410, AV704541, AV761412, AV702343, AV706814, AV709625, AV701499, AV762015, AV760106, AV703137, AV707043, AV762706, AV762631, AV707067, AV763298, AV762242, AV706025, AV733894, AV762852, AV764465, AV756702, AV709025, AV728138, AV701739, AV757334, AV705436, AW963592, AW955724, AV703844, AV704497, AV707654, AW962651, AV729090, AV702738, AW962006, AV755888, AV760048, AW957644, AW962942, AW963486, AV762009, AV761661, AV709897, AV729272, AV708388, AV712770, AV702109, AV711430, AV762082, AV705086, AV763847, AW958318, AV760908, AV725558, AV764034, AW963489, AW961593, AW966064, AW963552, AV701613, AW960468, AW956077, AW963463, AW962444, AV762067, AW953953, AW962268, AV727583, AV756508, AV703218, AV759768, AW961330, AV757526, AW963625, AV729411, AV705020, AV688823, AV710733, AV760724, AV683668, AV759352, AV763444, AV705532, AC002302.1, AL031273.1, AC005067.2, AC003982.1, AL022165.1, AC005225.2, AP001711.1, AC002470.17, AC012476.8, AC009060.7, AF196969.1, AC007917.15, AL354932.26, AC004148.1, AL359091.10, AC006059.3, AC005207.1, AC006312.8, AP001689.1, AC004824.3, AC007000.2, AC004840.3, AC011497.6, AC005229.1, AC006077.1, AC006480.3, AC005058.1, AC022543.2, AC004263.1, Z82184.1, AL445483.13, AC005632.2, AF134471.1, AC005859.1, AC002477.1, AF258545.2, AL024498.12, AC010458.5, AL136418.4, AL139054.1, AC002425.1, AC003007.1, AC006111.3, AC003692.1, AL096763.14, AL357497.17, AP001714.1, AL109743.4, AL118497.9, U15177.1, AL391384.18, AC005282.4, AC004089.25, AC011455.6, AP000089.1, AL132640.4, AP001630.1, AP000300.1, AC010319.7, AL136131.15, AC009137.6, AC010679.6, AC005015.2, AC018644.6, AL049761.11, D87675.1, AC007308.13, AL161779.32, AC005726.1, AC008599.6, AC009470.4, AC006121.1, AC011479.6, AP000113.1, AP000045.1, AF222686.1, AC004659.1, AC004000.1, AL158040.13, AC008745.6, AC004878.2, AL121914.31, AC004166.12, AC018755.3, AC019014.1, AC007003.4, U17576.1, AC010326.6, AC005052.2, AL354707.17, AC006038.2, AL008718.23, AL022476.2, AP001725.1, AL031282.1, AC007938.1, AL133448.4, AC018663.3, AC007216.2, AL117258.4, AC004867.5, AC006014.2, AC008891.7, AC007684.3, AC011489.6, AL353716.18, AL022302.10, AF312915.1, AC020906.6, AL354696.11, AC007991.7, AC007151.2, AC013726.7, AL359828.13, AL157838.24, AC005089.2, AC020928.6, Z68273.1, AC007021.3, AL161893.24, U91323.1, AC004149.1, AC008068.4, AP001717.1, AC010956.12, AL356214.20, AC020558.4, AL118520.26, AL139809.16, U67810.1, AL137162.25, AC003956.1, AL590109.4, AL049758.11, AL365364.19, AL392003.11, AL513366.11, Z97054.1, AC008395.6, AC013449.8, AL121983.13, AC004099.1, AL445687.5, AC004797.1, AC006329.5, AL158172.5, AP001695.1, Z95114.19, AC006449.19, AC008747.5, AC010388.5, AL049830.3, AC007052.4, AL135927.14, AC007227.3, AL022323.7, AC025097.41, AC005288.1, AC005808.1, AC078818.19, AP001716.1, AC005768.17, AC008551.5, AP000116.1, AL161630.12, AC006433.18, AL138920.11, AC007546.5, AC006511.5, AC004971.3, AC004851.2, AC008736.6, AL139113.21, AB038653.1, AC005372.1, AC005546.1, AC004913.2, AC008521.5, AC005291.1, AC005081.3, AC005255.1, AC007722.9, AL109613.11, AC005080.2, AC006120.1, AF141309.1, AL161936.15, AC005412.6, AL049713.20, AC018841.3, AC004106.1, AC007679.4, AC090426.1, AC013436.5, AC008166.2, AC004965.2, AC005098.2, AC008753.8, AL161757.4, AC008622.5, AC016691.10, AL136123.19, AC010519.6, AP002342.3, AC055731.22, AC006345.4, AC007066.4, AL158830.17, AC002544.1, AC011465.4, AC005519.3, AP000210.1, AP000132.1, AL021877.1, U95739.1, AL137017.9, AC005488.2, AC022211.5, AL355480.22, AL031587.3, AL031289.1, AC005995.3, AL353597.20, AC011462.4, AL138762.20, AC010976.5, AC006538.1, AC002310.1, AL161747.5, AL050332.15, AL034420.16, AC009477.4, AC005695.1, AL356481.16, AJ277546.2, AL138725.19, AL445237.16, AC006208.3, AJ009613.4, AF288742.1, AC007282.4, AC011443.6. HNHKV56 158 800877 1-1639 15-1653 H86448, AC009396.5. HOACG07 159 792928 1-1284 15-1298 AL529455, AL527447, AL519665, AL530298, AL526667, AL520518, BF312602, AL527270, AL523402, AL525526, AL525575, AL532418, BE795641, BF689773, BF690313, AL532417, BE793892, AL523401, BE798089, AW961032, BF978883, BE794106, BG117486, AL517000, AW375519, AW375527, AI761506, BF836264, BF237461, AA738047, AU123303, AI744657, AI573291, AA058761, BE259536, AI765107, BE502073, BF087384, BE888732, BE779165, BE394031, AW246799, AA700013, AW631125, BE786533, AA759011, BF315852, BE515115, H38495, BE889852, AI375009, BE702984, AI587531, AI148268, AL516999, AI809308, AW250662, T15960, AI890594, AI298775, BF102631, AA838498, AW137267, AI798469, AA838214, AI825338, AI200417, AU149319, R00301, AI085034, AI436070, AA036978, AI040364, AI537302, AA587887, AI341279, T99954, AA588536, AI368583, BG171023, AA366003, BE536848, AA573353, AI357177, AI474992, BG178921, AW872754, AI248063, AW337164, AW082916, AW663937, AW589264, AA830722, AA719102, T85297, AA683570, AW473394, AW630338, AI927184, AI500302, H78131, AI991231, BE644792, BF055078, AI766544, AI365563, T32118, AI344370, AI469218, AI370730, AI668957, AA036979, BF591154, AW973504, T85508, AW404558, AA365119, AI739608, AI263592, T98466, BG231108, AW663122, AA338808, AW167738, T98407, BE788568, F31030, H27770, AA434441, AW103958, AI364615, AI347419, AV756067, BF436680, BF436679, AK000557.1, AK022713.1, AK024220.1, AL109804.41. HODBB70 160 520196 1-590 15-604 AW079904, AW207285, H18498, R37566, BF852425, BF102683, AC006322.2. HOEBK60 161 789396 1-2204 15-2218 AL515934, AL520231, BE618778, BE618245, BE782129, BF056891, BG121474, BG250670, BG168174, BE905489, AI633878, BE042542, AL518067, AW515316, AW088411, BE536123, BE218306, BE644805, AW207435, BF087512, BF570490, AI818209, AI752319, AW962355, AL536159, AI669659, AA902264, AW105148, AW410334, AW083012, BF515266, BE465947, AL518068, AI927938, BG260989, AI420205, BE465917, AA043792, AI743602, AI283114, D81907, AL515935, BE546476, AA186486, AI417561, AU131122, N66098, AA573278, AA431514, AI752320, H14424, R59054, AI819645, AI631297, W00707, AI434568, BE221654, BF104164, AA973972, R59803, AA350599, H11851, AA724174, R17805, BF924661, H19130, AI638738, AI440413, N98699, AI702887, AA431188, AA280575, BF838288, R61472, AA653570, R77568, AI753861, C00128, BF998349, H29435, BF377857, AA348799, R18745, AI962149, AA809488, D78858, AA305344, AA360504, BF837084, BF352331, AI440138, AL135399, AA300827, AA329088, H83314, AW089455, D62361, AW811797, BE889780, BE561984, AI925346, BF374906, D78824, AW796219, AW811796, BG027920, N55732, BG036911, AW796258, AW410333, N90043, Z25249, R61473, BE899608, AA043666, AA174177, AA350598, BF089446, AW514435, AA095955, BF089445, BE736007, AA092014, AA096434, AW275782, AW275777, AA427677, AI624981, AI749472, AA704575, BE171096, AL044986, AW089135, W19853, BE940131, BF514239, BE163882, BE163878, BF243117, AK023143.1, BC004183.1, BC007219.1, BC000935.2, AK001928.1. HOFMO16 162 596835 1-1128 15-1142 HOFNB74 163 762821 1-1022 15-1036 AL528391, AV705461, BE742621, AW957840, AW957916, AA313780, AA469996, BF699406, BE897665, AA206557, N31702, AA459482, BE790325, BE899574, AW971024, AA460494, AI052029, AI761638, H55824, AA628498, AA412069, AI027538, AW514954, AI884599, AI419408, AW469200, AI992152, AA024623, AA581877, R62921, AI142045, AI275439, AI066572, AI939991, AA328484, AW002064, AA025955, W73635, W52125, AA492218, AL513597, AL514791, AL514935, AV723772, AV682289, AA954252, AW080838, AW166645, AV681668, AI906328, AI149592, AV682266, AL514087, AI907070, AI815383, AI220734, AV723204, BG108147, AL515047, AL514473, AL119049, AI624859, AV758217, AV756703, AV681857, AL515373, AV758592, AV758738, AL514627, AV682441, BE619513, AV723062, AV693157, AV733397, AL514543, AV705644, BF724691, AV682351, AV710479, AL513803, AV706777, AV661310, AV708119, AA328485, AV682479, AV730922, AV755581, AV681630, AV682252, AV682772, AI345860, BF673434, AI590482, BE777769, AV682051, AV758110, AV757205, AV682330, AL523243, AV682099, AA022458, BG058208, AL536633, AV682335, AI682106, AW132121, AV756477, AI907061, AL516344, AV729334, AL514359, AL524807, AV682466, AV711509, AV682385, AI525064, AV682521, BG108324, AL514075, AV682496, AV734638, AI349772, BG105099, AV734425, AV681586, AV681951, BF732407, AV733470, BF037607, BG109857, AV729701, BG259801, AV711355, AL513985, AL513907, BF940608, AV682249, BF725868, AL513763, AI345111, AI344182, AV661309, BE881155, BF795712, AV682809, AV681858, AV733824, AL513817, BF054789, AV711924, AV681872, AV682645, AV757096, AW168591, BF982085, AV755207, BE966443, BF107577, BE208710, BF348329, AL047042, AI569870, AV681949, BF726322, AV682222, AW071349, AW467961, AV734318, AI524991, BF791874, AV723953, AL514803, AW827203, AL513631, AV682476, AV758806, BE891101, AL519188, BG109125, AV704350, BF968041, AL513719, AL514657, AL514085, BF916588, AV734180, AV729890, AV655645, AV695052, AI207510, BF036115, AL514691, BE613622, BF337043, AL515041, BG120135, BE048026, BF339420, AI868831, AL514823, BG257535, AI349645, BG259943, AV724569, AA528822, BG179633, BF981774, BG109969, BE047863, BE966577, AV693410, AV732941, BE878186, AV704928, AI909662, AL513693, BF340104, BG033403, AV755614, AL121270, BG179993, BG254754, AI340582, AL512733.1, S78214.1, AL133640.1, AF090934.1, AL442072.1, BC008387.1, AL389978.1, AL050393.1, AB048953.1, AL049938.1, AF090900.1, BC007021.1, AB056809.1, AF078844.1, AB055303.1, AF090943.1, AL136586.1, AF125949.1, AL050146.1, AL157431.1, AL117457.1, AL133016.1, BC008417.1, AL442082.1, AL110196.1, BC008365.1, AL122050.1, AL137527.1, AL353594.13, AL117460.1, AL136787.1, AB056420.1, AL133606.1, AF090903.1, AF090901.1, AB050510.1, AF104032.1, AJ242859.1, AL133258.16, AK026608.1, AF218014.1, AK000212.1, BC008488.1, AB049758.1, AL080060.1, AL390167.1, AL359596.1, AL359601.1, AL049452.1, BC003687.1, AL110221.1, AL136749.1, AF106862.1, AC006336.4, AB063046.1, AL136789.1, AF111847.1, BC003683.1, AB047615.1, AL096744.1, AK027868.1, AL162006.1, AB060887.1, AF090896.1, AK026865.1, AB048964.1, AL050149.1, AL136892.1, Y16645.1, AB063070.1, U42766.1, AK026741.1, AB019565.1, AL050116.1, AB055361.1, AL122093.1, AB060916.1, AC005940.3, AK025339.1, AK025084.1, AL050108.1, AL499604.9, AL121952.18, AB060908.1, AC010879.2, AL445236.22, AB056768.1, AB063008.1, AL049430.1, AF091512.1, AL162083.1, BC001967.1, AL133075.1, AC005225.2, AK026045.1, AK025958.1, AL049314.1, AC026787.4, AC007375.6, AL049776.3, AL133344.28, AB048974.1, AB047801.1, AL049466.1, AL034374.2, AC026464.6, AL035067.2, AL136799.1, AC006357.5, AC007172.6, AF219137.1, AL353802.14, AL050277.1, AC007298.17, BC006807.1, AC006435.7, AL133557.1, AL080137.1, AC026307.16, AC004686.1, AC005886.2, AF097996.1, AL360294.11, AC010077.1, AC020558.4, AL080124.1, AC007043.3, AL137283.1, AC000111.1, AK026855.1, AK027096.1, AC002464.1, U95739.1, AC009145.4, AL389982.1, AC006039.2, AC024247.4, AK026744.1, AL122123.1, AL133093.1, AL133080.1, AL136844.1, AC005000.2, AL133565.1, AC004690.1, AL137459.1, AL035587.5, AL136768.1, AC006371.2, AL512746.1, AC021325.5, AP001699.1, AC020921.5, AK000618.1, AC005291.1, AL122121.1, BC002733.1. HOHBO66 164 853375 1-1776 15-1790 AL514591, AL515698, U51698, BF980392, BF525362, BE545041, BG119652, BF662991, AF142580, BF529862, BF792819, BF316356, AV661861, BE275539, BE897634, BE275581, BG120250, AW753619, AW369740, BG231720, BE514934, BE314321, AA625561, W72325, BF924219, BE646294, AW190127, AI744539, AW960688, AW958482, BF096207, BE843905, AI818046, BE312780, AI148823, AI911887, AI761511, AW250827, AI339159, BF242343, BE090100, AI092249, BF326698, AA210991, AA579979, BE275606, AV716564, AW402371, AW602002, BG249561, AA805668, BG109287, BE875739, BF576896, BG249196, BF032924, AU132598, BE889104, BF672317, AV714064, AV715127, AV717621, AV714198, AV713907, AV713990, AI207612, AI133220, AL038985, AV649250, AV734219, AV647955, BE909562, AV714647, AV714027, AV715811, AV714612, BG036237, BE677625, AI444571, AU127994, AL529892, BF673104, AV757743, AV714698, AV715067, AV715230, AV715535, AV717773, AA290643, AV711261, AV756185, AA305186, AV758452, BG035774, BE904072, AV714134, AV714607, BE259652, AV651042, BF691355, BG114310, BE780254, AW068844, BE877190, AV662310, BF037876, BF344767, BF674367, BE778740, BE880308, AV715907, BF576638, BG166184, AW844714, BF574463, AV716682, AW389525, BE504100, AW081185, BF215518, BE710295, AI907843, AA082142, BG115853, AV759509, BF923164, AV647965, AV661959, BF094085, AA309569, AW629881, AA310090, AL529891, BE543758, BE789752, AA157603, AA099988, BG249323, AI095655, C05087, AW068734, BF575823, BF790790, BF671005, BG109150, BF576248, BF672024, BF672662, BF574185, BF577139, BF574300, BF790442, BF576389, BF695048, BF575488, BF790998, BF575157, BF694795, BF672042, BP791268, BF670595, BF576658, BF575173, AW958488, BF574330, C03538, AV756552, BE385539, BF670646, BF694761, BF577293, AV691857, AI750264, W01220, AI337237, BF895630, BF574154, AI439571, BF672008, BF694739, BF791085, BF576584, BF672304, BF694929, BF671530, AA211386, BF670511, BF895656, BE563574, BF672207, BF672469, BF575743, BF693801, BF576235, BF693634, BF770271, BF895652, BF895621, AA215507, C18886, BF576736, BF791114, BE543762, BF672786, BF576071, BF574872, BF672725, BF577134, AA337932, BF895657, BF790905, BF692924, BF671342, AI357128, BE709306, BF694724, W74391, BF693794, BF895618, BF895653, BF576211, AW964198, AW069648, BE001231, AV729302, BF575558, AV649417, AV649433, AV649210, AV649443, AV647982, AV649192, BF672806, AV695866, BF895634, AA315723, BF575652, BF574446, AA383985, BF895626, BF672707, BF692921, BF574563, BF574420, BF575317, BF670554, AV649166, BF693840, BF577137, BF789916, AJ249940.2, BC000591.1, AK026173.1, AF083208.1, AC003103.1, X54304.1, BC004994.1, D50372.1, U26162.1, Z97183.1, AC005951.1. HORBS82 165 638293 1-1111 15-1125 AA716165, AW014086, AI675797, AI915560, AI093476, AI619556, AA346257, BG170965, AI674463, AI656676, AW962578, H26720, F32296, F33070, F24055, F23333, F32966, AI370391, AI446003, AI560806, AA857847, AW130863, AI282355, AI241901, AI889818, AI611743, AW243878, AI619502, AI630928, AI953765, AW083804, AA504514, AW081179, AA814782, BE967273, AI554821, AI620056, AI285735, AW262983, AI355849, AI245332, AI018686, AI635464, AW183620, AW020095, AL036187, BE966547, BG105445, AL036509, AI680498, BF970652, AW149869, AI433611, BG181012, BF914091, AI271796, BE621256, AV702932, BE962857, AI824557, AA555145, AA449768, AL513697, AW089009, AI368579, AW020592, AW130403, AL514823, AW022494, AW020288, BE785348, AL513817, BG108350, AW073996, AA937558, AV724929, AI863321, AI684127, AW075648, AW082997, AL514035, AI811911, AW168485, AV705811, AW083825, AI972170, AI537045, BE964576, AV734654, AI815239, BE964792, AI434833, AI301507, AI687168, AI289791, AL513693, AA808175, AL513911, BF763498, AI918634, BE965014, AI623736, BE965891, AI952249, AI862139, AW081343, AI923768, AL513809, AI050666, AI367210, AW170725, AA835947, AW025412, AW082040, AW025279, AW079045, AL513789, AI432532, AI874189, AI289608, AI536685, AI680113, BE965031, AW189268, AW827211, AW082623, BE965053, AI560023, AI439762, AW029611, AI978720, H89138, AI801592, BF339322, AA603709, AV659322, AI925404, AI627714, AW008090, BE735370, AW075519, AI866691, AI559737, AI921753, AI718161, AI582932, AI872545, AI446809, AA904121, AI251434, AI784214, AL514357, AW193467, BF338782, AA983883, AA480074, AW075482, AL514473, BG179586, AL514557, AI804983, AI697045, AL514691, AI924971, BF338027, BE299813, AW085373, AA514684, AL513553, BE966571, BE963909, BE964150, AI915207, BG178911, AI469516, AW151835, BF968679, AI475394, AI568114, AL514627, AW151850, AI457369, AI824648, BF038804, BE965481, AI375730, AW085667, AW192245, AA493923, AW059713, BF025686, BE878953, AI640379, AI498579, AI888665, AL038778, AW162189, AL515235, AI744243, AI691088, AW073868, BE964967, AI933940, BE613727, BE875442, AL514929, AW161202, AI961590, AI680435, BF968622, AI873638, AI863082, AL514455, AI915295, AL514101, AI859644, AW088944, AW089327, AI658566, AW806761, AI564186, BG179099, BF526494, AL513723, AL514983, AI811168, AL514089, AL514871, AW082060, AI925463, AL513779, AI952542, AI285439, AL514409, AI812107, BF971669, AI619751, BF904248, AI635478, AL514721, AL513999, BG105501, AI628325, AW020710, BF525392, AL513823, AI745713, AL034419.22, AK027081.1, BC002777.1, BC004926.1, AB063046.1, AF090900.1, AK000598.1, BC003591.1, BC003682.1, AK025099.1, AB047953.1, AL353957.1, AC004987.2, BC002495.1, AK025906.1, AF303581.1, AF178432.1, AC008592.4, BC003410.1, AK026528.1, AL133088.1, BC008708.1, AB060826.1, AB048910.1, BC004943.1, AB063071.1, AL050170.1, BC000799.1, BC005805.1, BC006164.1, AL136789.1, AL162062.1, AK026045.1, BC007517.1, BC003687.1, BC009311.1, AB052191.1, AL121916.14, AL389935.1, BC001294.1, AK027121.1, AB050510.1, AK026590.1, AL080074.1, BC001470.1, BC001236.1, BC002373.1, BC001328.1, AB060929.1, AL353956.1, AK000636.1, AL359624.1, BC004908.1, AB055303.1, BC007522.1, AB060887.1, BC006832.1, AJ004832.1, BC000066.1, S77771.1, AJ406937.1, BC001418.2, AK025375.1, AF179633.1, BC008649.1, AF245044.1, AK000432.1, AF141289.1, AB049892.1, BC008718.1, AK024974.1, AK027142.1, BC008983.1, AC007383.4, AL133640.1, AL137523.1, BC007453.1, AL137480.1, AP001346.1, AL110221.1, BC000054.1, AL137495.1, AL136925.1, AC004213.1, AL161802.15, AC006112.2, AL354828.12, AL035458.35, BC009033.1, BC001774.1, BC007248.1, BC005816.1, AL122111.1, AK027193.1, AF369701.1, AK026551.1, AL035407.15, AL356859.12, BC001801.1, BC002752.1, Y00093.1, BC006345.1, AK024747.1, AB049758.1, AK026855.1, AK024538.1, U77594.1, AB060229.1, BC007031.1, AK026542.1, AL080057.1, BC000008.1, BC000386.1, AK026480.1, AK025084.1, AL157464.1, AL080127.1, AL137705.1, AL121601.13, Z49258.1, BC002733.1, BC002491.1, AB049848.1, AF217973.1, AF239683.1, BC002409.1, AC006451.5, BC003105.1, AL157360.8, Y14040.1, AL389978.1, BC002839.1, BC009395.1, AF067420.1, AP001731.1, AK027154.1, AB060881.1, BC002471.1, AL137711.1, AB050431.1, AK024855.1, AF274348.1, AF274347.1, AF352728.1, BC006087.1, AL353940.1, AF004162.1, AL050092.1, AL136787.1, S76508.1, X53587.1, AF232935.1, AL132985.4, BC004481.1, BC008507.1, BC002344.1, AF094850.1, AP001666.1, BC001099.1, BC004431.1, AL133010.1, Z94277.1, AL137556.1, BC002399.1, BC003104.1, AK025209.1, AF110640.1, AF120268.1, BC008788.1, BC007534.1, AK026038.1, AC008507.8, AC026307.16, AC007172.6, AL031732.8, AC017082.4, AK026749.1, AF012536.1, BC007053.1, BC009026.1, BC002444.1, AF218014.1, BC001785.1, AC002540.1, AF225424.1, AK025414.1, AF217987.1, BC007355.1, AK027164.1, BC008723.1, AL512689.1, AK000753.1, AL121952.18, AL133062.1, AL136979.16, U91329.1, AF095901.1, BC007034.1, BC002958.1, AL080060.1, BC007389.1, AK026395.1, AL356747.18, AL590076.3, AF022813.1, BC004925.1, AC008897.7, AL137461.1, AL080110.1, BC006196.1, AL117585.1, AL136843.1, S69510.1, AF044323.1, AK026526.1, BC002574.1, AL355143.17, AL157878.11, AC020956.6, AF358829.1, AF028823.2, AF162270.1, AB060893.1, AK026518.1, AF177336.1, AK026793.1, AK026630.1, BC006287.1, AL136586.1, AF321617.1, BC006465.1, AK000647.1, AK026649.1, AC005968.1, AK000450.1, M19658.1, D83989.1, AL049464.1, AF073483.1, AF217989.1, AF217966.1. HORBV76 166 839270 1-1143 15-1157 BF982706, AI571494, AI888858, AA703510, AA128464, AI091675, AA129916, AW613716, AA569492, BE937241, AW301397, AW301415, AI637838, BF056511, AW082378, D12398, AA325607, BE879070, W93799, BF091683, BE170912, AW051087, AW089279, AW935039, AA910432, AB017165.1, AC005971.5, AJ009616.3. HOSDO75 167 862049 1-888 15-902 AI375670, AI990134, AA732220, AI494146, AA172039, BE777959, AA258154, AI394315, BF086933, AA172291, BE093382, AA456756, N57268, BF086946, AU138426, AU139896, BE093384, AA113041, AA258916, AK002100.1. HOSEI81 168 562778 1-883 15-897 AA418350, AA418237. HOUDE92 169 580866 1-1270 15-1284 BE736091, BF237553, BE781264, BF686547, BE313480, BE872070, BF313936, AI138711, AI348027, BE502126, BE258631, AA524244, AW873570, AI982983, AI367855, AI052179, N90758, AA325647, AW419076, AW873111, AW008195, AI304671, AI367495, AW964887, AI609692, AA019213, AI279349, AI581275, AI224904, AI141287, H14110, H41440, AI017367, H29060, H29163, AA482386, AI471043, AI742262, AI262559, H52568, AA872715, R60248, H06091, AI041676, BE856821, H86160, H86771, AI241156, AA872384, R60761, AW131262, T31006, H56455, H95225, AA535480, AA678522, AA953998, R93546, R47352, BF968234, C04826, N39943, AA779062, T31180, H69216, AA017105, AA738315, AA019233, C04344, C05015, H17526, R99865, H84704, AW025505, AA057567, N72695, H86419, W02476, N27200, AA001522, AW194286, AI264419, AI220672, AI290418, T30927, AI620442, AA985424, R49316, H86772, AA725465, R91429, R93547, AA017106, AI074855, H95701, H69217, H95226, AW188581, AI678424, AA057566, AA326095, AA976949, H56456, W57713, AW166317, Z42112, AA775239, AI864069, AA918031, H85105, AA015626, AA977988, AA429622, R99866, H14085, AI000910, AI431360, Z38375, W57838, AA015625, R57558, AI949351, AI262422, AC005865.1, AF217967.1, AK027366.1, AC005912.1. HPCAL26 170 762822 1-3083 15-3097 BG164171, BG171313, AW338908, BE327883, BF058325, BE856282, AL525344, BG027433, AA621714, AL047905, AW780148, AI633775, BE973735, AW438611, AI755212, BF381979, AW337238, AI337968, AI963595, AW572336, AA432021, AW471145, AW069566, AA448477, AI936887, BF108841, AI829408, BE748629, AI042324, AI955816, AI421409, AA758227, AA814190, N91448, BF030663, AW192439, AI683517, AA417975, AI129364, AI561083, AA418135, AI088536, AW628520, BE327874, W72280, BE878275, AI348236, AI088467, N26180, AI628017, AI066421, AI346288, AI142951, AI308778, AI446338, AA458899, AI078536, AI346382, AI753070, AA923036, AI431409, AI087120, AI341640, AI567761, AI371263, AI754690, AI285250, BE619821, AA630948, AI354829, BE620033, AW294799, W45027, AI902379, AI537262, AI866883, N27411, BE876666, BF338393, AI963351, AI081820, BE395375, BE620777, BE906942, AI811301, AI627940, AL538418, AA602460, BE548617, BF038519, AW205903, BF893012, W76307, AA701166, AL525384, AW023777, AW956752, BE122762, AA128212, AI094190, BG163634, AI371264, AW856743, AW380612, R81003, BE905099, N23359, BE619502, AI589929, BE905025, AW469305, AI254707, N67744, BE619375, AA961234, BE906749, BE784570, BE909607, AW387116, BE904894, BF695306, W25857, AA134565, AW044064, AW802015, BE673511, R76732, AI392841, BF509258, BE503655, BE880509, AI299995, AA304323, AI074674, BE788330, AI086914, AA383490, AW630488, AA977524, AW802237, AA296648, AA431796, AA047280, AA813746, AW236745, AA193605, AA127172, AW080334, AI696769, BF437027, BG167009, AW361256, BE938690, R76394, BE218539, R39674, BF475923, BE843065, AW819110, AW819102, R39598, R80801, AI540488, AA134564, AA193568, AW818988, AI245052, N55215, BG120706, AA307251, BG119547, BE843137, BE816369, AW957969, AA776346, AW819052, C01782, AW517411, AI906011, AA303350, T24798, BF799939, AW603344, BE748082, W39532, BE543246, AA047141, BF800032, N34692, BE168974, AA340956, BE620236, BE937574, BE122763, AW818992, AA304405, AF193611.1, BC001278.1, AF015287.1, AL136914.1. HPEAD23 171 773409 1-568 15-582 BG037089, BF973374, BG025260, BF981319, AI827721, AI220233, BE876017, AA910948, AW663886, AA728767, AI279770, BF727458, AA972390, AI051448, AA932444, AI346841, AA740783, AI186713, AA948231, AA905780, AA918553, AA884145, AI268749, AI346070, AA858123, AA857640, BE275406, AW025402, AI262503, T95182, AL389983.1, AK025239.1, U90913.1, AF234997.1, AF028823.2, U78525.1, AL137298.1, AL389943.1, AK025254.1. HPEBA84 172 753957 1-1146 15-1160 AV702197, AW964983, AI283912, AV688589, AA679863, R77836, AA112690, AI686145, AA342049, AA658167, AA112689, AA640275, AA342050, BF876992, AL161799.19. HPFCI36 173 855966 1-865 15-879 AL516624, AW967335, AI346493, BF969871, AI379068, AW813968, AI435632, AW439597, AA160513, AA111896, AI129000, AI803023, AI587653, AI247913, AW080897, AA111878, BF197837, T58186, H04232, W07286, BE243262, BG165835, AA046003, AW028757, BE882257, BE393612, AA357180, AA085677, AA085834, AA621577, R36594, BF733978, AI014838, AL536330, AV753531, AV751871, R36593, AV752854, AW605869, AA341976, T58072, AW955926, AA576671, BF825158, BF245058, AL527071, AI367586, N79788, AA321931, AI566375, AI709192, AW379008, AA441898, AK000452.1. HPFDI37 174 862056 1-338 15-352 H55085, AA434130, R25258, R20029, H14658, AW950901, BE275081, R19886, BE727676, BG248105, BF345809, BE730221, BE904350, AC000090.2, AF106697.1, BC007489.1, AF171054.1, AF044212.1, AF166126.1, AF166127.1, AB019694.1, AB019695.1, AF201385.1. HPIAA80 175 829972 1-905 15-919 BE865466, BG170320, AW043782, AW662099, AI933030, BF432372, AI553724, AA629903, AW341957, AW073315, AW972918, AA542856, AA380138, H22229, BF667499, C02428, BF573889, BF695553, BF697671, BF982558, BE694971, BE961006, BE865295, BF507508, AW467509, BF571682, AW372886, H25153, AA302738. HPJCW58 176 612866 1-1151 15-1165 HPMCV30 177 612870 1-894 15-908 BG122182, BG034611, BE548730, BG110667, AW205272, AI800593, AI802988, F25189, AI740610, N23684, AW470648, AL120942, BF530954, AA890692, AI352429, AI634593, BG060184, AA554454, BG255820, AU145072, AW026128, BF431915, AI937808, AA593782, BF436462, AI826416, AI362153, AW071745, BF345276, BG107551, F28025, AA629269, AV762395, BF527699, AI216789, BG059451, N33439, AI362065, F37490, AI721014, AW874543, D52077, BE208411, AL042101, F25151, AI144207, AI423120, AA229607, F24889, F20765, AV761362, F30834, R84504, T27765, AV763971, AW006041, AI334443, BF668217, AL119691, AV763418, BF766630, AU147922, BG060172, AA523503, AW975164, AI720758, AA302029, AV759935, BF241967, BF677892, AF177861, AV763540, BF477449, AI284640, AV744105, AV761489, AI061361, AI904894, AL046409, BF982691, AI053445, AV744733, AI865213, AV762111, AV763255, AV735370, BF984558, AV741390, AI963720, F25232, AV761786, BG249643, AV759274, BF674369, AI289199, BF475381, AI679782, AL138455, AV762098, BF919090, AI500671, BF918590, AI004246, AA581903, F16559, AI306630, AI291821, AI792287, AI284007, AW193265, BF793766, AA703891, BF792268, AI431303, AI708009, AW274349, AW970571, AW303196, AI252506, BF701281, AV762826, AA302020, AL041690, AI613280, AV682003, AA501614, AL037910, AI370475, AW473163, AV702609, AV706237, AV763401, AI133164, BF915839, F19506, BG230879, AA954712, AW301350, AV760937, AV763354, AA308136, AF330238, BF337291, AA374320, AL044940, AA320811, AV758722, AW472872, AW438643, AI345654, AW021583, AV762397, AW265393, AV762139, AA469451, AI350211, AW075979, AW406447, AW662543, AA872171, AV759967, AV713291, AW500125, AW515448, AW504485, AI623899, AW872676, BF681619, AI281881, AW088846, AI281903, AW974109, AW021207, AL046205, AL045709, AI418972, AV710066, AI270117, AV762505, AV764307, AI272314, AI273107, AA491814, AW407578, AI890348, AV762064, AA490183, AW276827, AV760057, AW276435, AA523497, AV763670, BF725347, AI343143, AV761843, AI754253, AV762009, AI927380, AA521323, AA494038, AI696962, AW327868, AI345681, AI345675, AW338086, AV761925, AV703682, AI471572, AV658688, AW576287, AW302013, AW162049, AI246119, AA720702, AV762050, AW963497, AC005517.7, Z11692.1, AL049780.4, AL135928.6, AC008372.6, D83989.1, AC009228.4, AP000552.1, AF196969.1, AC004067.1, AC016620.6, AL139415.10, AL033529.25, AL133163.2, AL139113.21, AL031295.1, AC090955.2, AL445686.14, AC019046.4, AC008543.7, AC009131.6, X55926.1, AL031296.1, AL445205.14, AC012076.4, AL121989.12, AL359091.10, AC009077.7, AL049759.10, AP002007.4, X54175.1, AL449209.2, AL034405.16, AL158207.15, AC006312.8, AL133371.3, AC018751.30, AC005755.1, AC021999.4, AC020754.4, AC003049.1, AC009996.7, AL355922.4, AC009516.19, AL137792.11, AL590031.6, AL590762.1, AL121653.2, Z99127.1, AF129756.1, AC005701.1, AC018755.3, AL353716.18, AC011495.6, AC023490.5, AC006160.9, AL161937.13, AL118520.26, AC007546.5, AF053356.1, AC005261.1, AL355916.2, AL158055.12, AL513008.14, AC006077.1, Z85986.1, AL049776.3, AL139045.12, AL161743.20, AB060227.1, AC004805.1, AL121601.13, AL137784.14, AL109935.39, Z82190.1, AC005821.1, AL034550.31, AF015148.1, AL117328.5, AC005740.1, X53550.1, AC006334.3, AC002544.1, AL356756.4, AC078818.19, AC004909.2, AP000556.2, AC078962.30, AL109804.41, AL118556.4, AL133347.28, AC026882.5, AL391827.18, AL354932.26, AC011514.3, AC012309.7, AL136418.4, AL139054.1, AL356378.17, X54181.1, AC003043.1, AL138720.19, AC007055.3, AL096793.20, AL137073.13, AC005841.3, AL133545.10, AC002300.1, AP001760.1, AL353738.16, AC004068.1, AL121808.4, AC005632.2, AC006130.1, AL358777.12, AC004819.1, AC010620.4, AC020916.7, Z85987.13, AC005484.2, AC003684.1, AC005832.1, AP000339.1, AC006211.1, U67221.1, AL160269.14, AL034417.14, AC084865.2, AC002350.1, AL161896.16, AF077058.1, AC027129.5, AC010271.6, AL161626.20, AL450487.17, M19997.1, U57007.1, AL133458.19, AL355136.19, AL109921.21, AC003101.1, AC008132.35, AC005064.3, AC008440.8, AL451107.6, AL121825.19, AC007432.9, AC004873.3, AC005324.1, AC008747.5, AL139109.14, AL138724.12, AL161672.13, AC020898.5, AL157951.5, X51466.1, AC024082.6, AC007405.6, AL359235.3, AL135924.11, AC005288.1, AC025435.5, AC005694.3, AL132713.11, AL355499.15, AL008715.1, AF001550.1, AL139809.16, Z82180.19, AC012330.8, AL024498.12, AL136992.22, AC023491.21, AL160471.5, AP001732.1, AP000474.2, AL031120.1, AL139317.5, AL034423.21, AC009137.6, AP001725.1, AP000514.1, AC002351.1, AL132768.15, AC025593.5, AC003036.1, AC073651.23, AL117694.5, AL158040.13, AC007981.46, AL138976.5, AL137068.10, AL122058.19, AL359644.10, AL353579.17, AL031315.1, AF334404.1, AL161444.18, AC009309.4, AL022097.1, AL445664.14, AC012444.9, AP000558.1, AC000052.16, AC005887.3, AC002418.1, AC078994.3, AC002470.17, AP000504.1, AL031659.9, AC004386.1, AP000356.1, AL391833.10, M37551.1, AC009244.24, AF015151.1, AL390239.16, AL020993.1, AL008721.1, Z97832.11, Y18000.1, AC015541.21, AC026162.5, AC005020.5, AP001426.2, AC005041.2, AC005251.1, AC018816.5, Z97055.1, AF181897.1, AC011473.4, AL135978.4, AC005598.6, AC006251.3, AC004019.20, AC008760.6, AL391262.3, AC005179.1, AC025265.21, AC018641.3, AC034242.5, AL109963.4, AL035448.29, AC024085.5, AL023879.1, AL163201.2, AC005274.1, AL034380.26, AC011477.5, AC002310.1. HPRBH85 178 695752 1-1659 15-1673 AI147467, BG252600, BF354490, BF354491, BE999965, BF032961, W52563, AW512426, AI810178, BE274472, AI188557, BF432115, N25987, AI700626, N29859, AI659619, N29340, AI031999, AA974460, AI267374, BF593262, N36618, AL538054, AI350777, AI656701, AV724003, W01296, AI949788, Z39752, H09136, AA234945, W60255, AA635309, Z43693, H09192, AI583723, BE830918, N67638, AA371469, AA706920, AI537632, AW028490, AI799012, AA234944, R34999, T64063, AA855109, BF082755, BF332778, BF082768, BF082759, BF082766, BF328302, N57281, AW301576, AA610602, BE181224, BB830920, R49386, BE009565, BF332781, T63991, N83625, AA495939, H26811, AI348901, AI564500, AL039274, AW051088, AI866469, R41605, AL514691, BF871314, BG029058, AI889180, AW834282, AI433611, AW089844, AA806757, AL118781, AI370623, AI471429, AL039086, AI619525, AI628325, AA464646, AW076124, BE875959, AI345688, AI583558, AL121365, BF033757, AL048351, AI285439, AI638644, AI621341, AI524654, AL046466, AI474646, BF970162, AW195253, AW020381, AA808175, AV704934, AV750565, AI445069, AI619820, AI537677, AI874107, AI309306, AI927233, AI891084, AI589428, AI472487, AI270183, AL079963, BG169738, AW083572, AA806719, AI859464, AI951123, AI634457, BF812960, AA470491, BE906646, AI475371, N92140, AW827107, BF811808, BF750886, AI684127, AA654216, AI972070, AI473536, AV734747, AV733582, AI590755, AW150557, AI499963, AI932503, AW192300, BE393784, BF971340, AW050850, AL046595, AA825826, AI582932, AI923989, BE909549, AI978703, BG250575, BF525577, AI536685, AA857847, BG253684, BE892118, AV701597, BG170663, AW080140, AV682112, AW025279, BG260760, AW021091, BF796402, AI923559, BG260287, AI610446, N25033, AI702527, BE966968, BG256090, BF970123, AI861973, AW088183, AI564212, BG034586, AA693331, BG034746, AL138376, AW023072, BF089679, AV726156, AW105087, AI866090, AI479292, AV682403, AW021256, AI932794, AV757018, BG255493, AW076127, BF527697, AA838435, AI560873, AI590043, AI440260, AV747571, AV656932, AI433590, AW029566, AI819976, AW020710, AI609331, AV762892, AI225000, AI357599, BF680133, AI954721, BG260524, AI815232, BF724651, BE877142, AL045950, BG026483, AW019988, AI566613, BF892007, AI524179, AI368691, BF766531, AW075382, AI567971, AW080076, AV682366, AI539260, BE047852, AW172745, BE439677, AW089275, AW020419, AI079736, AL039390, AI879377, BE536417, AI500061, AI306610, AW168875, AI537516, BE621256, AI799313, AI096771, T69241, BG250789, AV682250, AI225004, AI698391, BG113851, BF680131, AI741158, AK027690.1, AB050514.1, AL162002.1, BC008899.1, AK026959.1, AF155656.1, AF326206.1, AF265236.1, BC001967.1, AL137459.1, AK024747.1, BC006287.1, AF006516.1, AF117959.1, BC001236.1, BC002373.1, AK025113.1, AF245044.1, BC001964.1, BC003590.1, AL136882.1, AL389935.1, AL137480.1, AK026389.1, BC002733.1, AB048881.1, BC008946.1, X61970.1, AK027096.1, AL359583.1, X99226.1, AB051158.1, BC008708.1, BC009395.1, BC004925.1, AL137711.1, AF274348.1, AF274347.1, AK026534.1, AK024588.1, AL512733.1, X59812.1, AK025015.1, BC001199.1, AL136864.1, AB062978.1, M92439.1, AL137523.1, AL359615.1, AL137550.1, Y10080.1, AL110196.1, AB044547.1, AK027142.1, BC002476.1, AJ006417.1, AB055370.1, AF195092.1, AK026647.1, AF026816.2, BC009026.1, AF353396.1, AL136622.1, AK025906.1, AK026541.1, AF131821.1, AF044323.1, BC000778.1, BC003658.1, AL137657.1, BC008488.1, AK025209.1, Z37987.1, AL122100.1, BC005843.1, AK026434.1, AL117435.1, BC001328.1, BC000090.1, AL136586.1, X72889.1, BC003637.1, AK027129.1, AF056191.1, BC003122.1, AK026649.1, AK000647.1, BC004945.1, AB055361.1, AL049464.1, AK026626.1, AB060852.1, BC005854.1, AF205861.1, BC001670.1, AK026506.1, BC006807.1, AL133637.1, AK026633.1, BC008920.1, BC007364.1, BC000386.1, BC000643.1, AL080146.1, AL137478.1, BC008836.1, AL359596.1, AK025084.1, M85165.1, AK025092.1, AL512746.1, BC007767.1, S77771.1, AL136893.1, AL353940.1, BC001844.1, BC000235.1, AL050138.1, BC009398.1, X83544.1, BC000316.1, AL137267.1, AL137557.1, AL133080.1, AB060837.1, AL133049.1, BC000761.1, BC008673.1, AK026518.1, AK027146.1, AK026613.1, BC002466.1, S76508.1, AF227198.1, AJ406930.1, BC001082.1, BC005002.1, BC000751.1, AK027081.1, AK027116.1, AK024594.1, AK026057.1, AK027210.1, AL117587.1, BC001785.1, BC005168.1, AB056421.1, AL133062.1, BC002985.1, U73682.1, AY033593.1, BC006181.1, AL049283.1, AC009364.8, AK026462.1, AL137258.1, BC007375.1, AL389939.1, BC000007.1, AF111112.1, AL137627.1, AL512704.1, AK027152.1, AL136615.1, AL049382.1, BC006440.1, AK027173.1, Z82022.1, BC002343.1, BC006494.1, BC006345.1, AL137663.1, AF106697.1, BC007556.1, AL512718.1, AB060839.1, AK000250.1, AK000197.1, BC007420.1, AL050143.1, AL096720.1, AL157433.1, AJ406932.1, BC003410.1, AF285836.1, BC004297.1, AL137275.1, AL110280.1, AC002467.1, AC020908.6, AK026600.1, BC002491.1, AB060893.1, BC007255.1, AF114784.1, BC007852.1, AB048995.1, BC004874.1, AB052200.1, BC008078.1, BC001675.1, AK027136.1, BC005890.1, AF057300.1, AF057299.1, AL356103.8, BC007674.1, AL080124.1, AL133104.1, BC005858.1, AK024533.1, AK027137.1, AL122104.1, BC002541.1, AB050410.1, BC004951.1, BC007204.1, AL050172.1, BC007456.1, BC006196.1, AF183393.1, AK027164.1, BC002495.1, AK025632.1, AB050431.1, AB060888.1, AF061795.1, AF151685.1, AK000618.1, U42766.1, AL136787.1, AK000653.1, AF102166.1, X66417.1, BC000077.1, AB060229.1, BC004960.1, X82434.1, AL049339.1, Y14040.1, BC004991.1, AF159141.1, BC006091.1, BC008591.1, BC003591.1, BC002519.1. HPRCD35 179 853551 1-695 15-709 AI952238, BF966633, BE673553, AW249944, AW673164, AI491912, AI433456, AW027835, AI434093, AA040338, BG152387, AI744101, BF589019, AI433927, AW388710, BE710661, AW027844, BF951319, AW514110, BE893648, AW235679, BF951645, AA853738, N77918, BF904963, AW027796, BF951640, AI820008, BF802330, BF802123, BE091385, AA040337, D20818, BG116710, W07085, BE348578, BF979894, BF448283, AI806099, AA746652, AI269951, AI370493, BE251472, BG255671, BE743054, BE873348, AA034242, AI269933, AI494531, AA193194, R01841, AW130830, R71213, BE746974, BG252660, R01109, AV746580, AV709278, AA910706, BF204537, R94047, N62862, BF832992, AI828509, BE700205, AW899366, BF951647, AA323326, AL042486, AL527593, T97110, AW176293, AA886453, AA319188, AI521632, AV699431, BF922964, AV700764, AV700026, W26006, N93989, BF951643, AA193234, N87415, BF825093, BF841081, BE695594, BE695488, AV695783, AV692484, T69241, AA398143, AV682403, AV682366, BE907663, BG030601, BF978949, BF965959, AI801106, AL039456, AI499161, AI635132, AL359611.1, AK025633.1, AB037802.1, AK027681.1, BC002349.1, AK026408.1, AL133088.1, AL359583.1, Y10183.1, AB048881.1, AC011450.4. HPRCM72 180 813512 1-2441 15-2455 BG166460, BE883382, BF683382, AI341658, AW952999, BG163786, BE465453, AI338324, BE326569, BE464879, BF433097, BG261233, W46356, BF437934, AA149241, AI031948, BF445095, AA461239, AI655712, AI828045, BF666548, BE645287, BE218005, AA740917, AW089849, BE938758, BF038531, BE043103, AW162691, AV734920, AV713130, BF001984, AI338571, AA811891, AI830924, AI457882, AW081477, BF670487, AI694811, AI828812, AI811880, BF513545, AA769609, BE550664, AW450022, BE217994, AI458724, W94368, AV716605, AW172702, AA460935, AI332449, AA745014, AA807040, AI167711, AA701349, BF681205, BF541286, AW573067, AI571036, AI336394, AI458489, BF027933, AA864779, R63261, AI221414, AW511576, AA578272, AA805282, AA781586, W94477, BF110711, N50967, AW118243, AW630626, AA705280, AI081322, AA804627, AA505733, AI079516, N21046, N66225, AA620673, AW664752, BF700662, AI291751, AA743371, AI080702, AA976574, AA702877, AA830244, BF572889, AA121467, W46192, BF354049, AA121295, BF435675, AI873006, AA150022, AI216060, BE244500, BE865586, AI342791, AA325308, BF666155, AA586934, N98297, AI535871, AI766438, H82449, AW613882, AW085296, AI584035, AI224954, BG104548, AI276071, AI806750, AI682664, AA076152, AA832356, AA076057, T87592, BE765250, AA669771, BF208676, AW511081, AA860585, AW118242, AW959674, AA228738, AA995894, AI184762, AA830530, AW118244, H65071, AA492305, AI352669, H65630, AI095304, BF244857, BE775070, AW971029, Z43498, AI631433, BE243950, N92624, AA976997, T59146, AW517774, BE786488, H05855, AA345351, BE714157, BF247351, R21170, AA285079, AI383913, D79961, W38747, AI610582, AA890635, H79991, R93581, AA304798, N27877, T59184, AI869421, H05748, R22788, AI743377, L32010, Z39568, BE934528, T97283, BE301973, BF675995, AI933883, T97395, H79992, R07789, AW007681, R63213, AA044925, N76786, BE826985, AA150087, H65072, BE938783, AW748686, BF237813, BE768786, BE866492, R93582, BE844122, BE938793, BE938764, AA379573, BE173330, BG114724, BE700340, H03778, AK025902.1, AL110163.1. HPTRE80 181 884167 1-1159 15-1173 AI719545, BG248226, BE886380, BF116178, AW003531, BF207082, BG250696, AL044449, BE538221, BE784939, AI885407, AW246550, AA490655, AW024407, AW081534, AW960860, AW872780, AI870293, AI360297, BF036691, AA490654, AI921772, AI553796, AA613650, BE537572, AI673517, AI360358, AW082921, AW263806, AI417178, AA846693, AI214250, AA001318, AA374910, AI827461, AI560048, BE314431, AI340075, AI318298, AA595365, BE837126, AA580265, AI829934, AI085813, AI376538, H27782, BG007963, AA948279, AW074629, AW135529, AA910140, AA297010, AA857878, AW248341, AA832012, BF511306, AA297016, BF529929, BF244493, AA906871, T07218, AA568231, AA953262, AI383030, AW150846, AI140575, AW407144, BE884493, T30682, AW248342, AV727418, AF177385.1, U62317.2, AL021683.1. HPTRI42 182 655362 1-1084 15-1098 AL530013, BF689272, BF057597, BE780679, BE264598, AU159982, AU159148, AI889175, BE782348, BE867162, AW001971, AV660589, AI940395, AI589299, BE398067, AI808453, AA809956, BE397390, T15859, AI962984, H20543, AA235197, AI685406, BG056919, AA862809, BE514151, AI243558, AA995380, BF590659, AA962405, BE696154, BF868362, H20635, AW242465, BE504803, BF348076, BC001341.1, AL110260.1, AK023915.1. HPTRM02 183 812879 1-1746 15-1760 AL524458, BE738365, BE797125, BE799999, BG029222, BE745922, BE545163, BE907437, BE799866, BF305271, BE544399, BF663830, BE796881, BF308083, BG169861, BE350925, AW385462, BF307517, BE797270, BE743037, BF668016, BG180312, BF974123, BE737908, BF663981, AW247807, BE513095, BE906969, AL138083, BE255971, BF664455, BF338518, BF244474, AL536412, BG231717, BG121312, AW005562, AI357069, BF000625, AA644049, AL523557, AW513359, AA632166, AW246260, BF892728, AA706163, AL520864, BE746537, AW245080, AI879390, AA496904, BG177219, AW005067, AW276591, BE791039, AW804483, AA738041, BE747177, BF869837, BE251828, BE875024, AI088680, BE297879, BF948818, AA831030, BE559592, BE561590, BF340321, AW248071, AA860150, AA149920, T63138, AL524459, AW439742, AI609027, AW804577, AI659057, AW886264, AA193529, AA057835, BE743405, R73214, AW194065, BE562027, AW075497, R75945, BE559810, AA706533, BF894712, AI468114, AW249614, AA335528, BE795304, AA827797, AI302055, BF129302, AI750232, AA427422, BF930249, BE560497, AA860105, BF939406, AA335848, AW404930, AW571830, R76783, T15952, BE560176, BG152613, BE267829, AW991408, BE269966, AW991532, BF664249, AL138082, BE269643, AW575878, BE797429, AW071243, AA304216, BE791865, AW945716, AW875302, R37100, AA682206, BE277420, AA193433, AW751797, AA352416, AA587756, AI818900, AW518507, BE939890, AA852530, R07062, BE900192, BE296328, AA931598, BE671371, T32042, AI033227, AA353903, R82530, BG121259, AI281709, BE389644, H28650, AA534672, AA548317, BE866982, AW084505, R73151, AA349275, T62995, BF205162, AI219302, BF688975, BG117867, BE748125, BF128654, AW772768, R82480, AA665591, BF434544, AW246149, BE859039, AA687496, AW403743, AI738846, BF893795, BF772867, BE388333, AW874200, BE890138, BE791538, BG027900, BF129181, AI468932, C00531, AW150444, AW338439, BE388322, BF931213, AW875234, AW385458, AW991401, AW875290, AW373139, AW385460, AW581536, AW875235, AW875239, AA687440, AI948428, BE727787, AW403641, AW393066, AW875349, AW581529, AW875238, AW875305, AW875255, BE748665, AW875292, AW875249, BE383820, AW875301, AW581521, AW581531, AW875245, AW875307, AW875248, AW875296, AW875241, AW875360, AW581537, AW875368, AA653357, AW385464, AA852531, AI878829, AI079775, BF874873, BF991409, AW403272, BF772016, BF688505, BF592857, AW518551, AW991487, BG012697, AW835133, AW875362, AW962437, AA078519, AW581533, AF218020.1, AF151364.1, AF077353.1, AK027367.1, AF197060.1, AF250287.1. HPTRQ52 184 655363 1-644 15-658 AL527941, AL533906, AW247351, AI832791, AW245938, AI310124, AW674400, AW515975, AW675728, AL529035, AA226400, AU150370, AA569956, AW469172, AI245352, AI890679, BE300693, AI601125, AI962952, AA533187, AI221330, AI564190, W80352, AW188512, BE394504, AA040058, AA633700, AI208267, AI792211, AI215909, N90770, AA643585, BF221803, AI865794, AU138677, N30739, AW512882, N95345, AI890616, BG166982, AA349670, N59649, H91459, AA994951, BE265966, AA311285, AW731826, BF807476, AA037422, AA554209, T95955, BF240778, BF802840, AA176708, AW592984, AA737167, AA431700, AW006451, T95961, BF807473, AI352253, AI372503, AA229521, T95866, AA972235, AU158023, AI733502, BE767129, AA226924, AA323327, AW388658, AL046918, T95860, H13591, W26197, BE909498, BF476991, AA865022, AI148858, AA936123, BF371957, AA641404, AA876362, BF957886, AI905350, AA813410, AA173027, AI879823, AA876167, AA031577, AW518440, AI784024, AI015568, H54187, R77485, AW405360, AA031456, H13222, AA384005, AA470650, AI275659, W80351, AA431493, AA861578, N35164, AW513500, AW088915, BE241964, BE171388, R69693, R38031, AA054553, AW749739, W21999, AI378983, N78203, BF317122, BF205960, W25254, AI364635, BE546333, AI961834, BE770665, AA928539, AB026628.1, BC002773.1, AB018357.1, AK001420.1, AK024944.1, AL109672.1, AK027098.1, AL136913.1, AK000251.1. HPTVI96 185 636064 1-506 15-520 HPWBA29 186 561956 1-311 15-325 HRDAI17 187 560720 1-1486 15-1500 AW974589, AW867451, AA579866, AW965263, AA460591, AW298601, AA461519, H56628, BF845119, AA018544, AA331634, BF244465, AI630413, AV741309, AI254046, AW302016, AA661929, AI754721, AI255060, AI270853, AI252826, AI435754, AW086343, AW301997, BE857819, AI271005, BE139221, BE139213, AI254826, AW271081, AI224422, AI252060, AW302086, AI254783, AI307025, AI254056, AI254683, AI223591, AI252493, AA484479, AI362694, AI524022, AI251312, AI308320, AW237905, AW407632, AI141964, AA730035, AA678950, AV709139, AI189682, BF448904, AU146063, AW275432, AL037777, AI365618, AI206841, AW963594, AL047480, BF971214, AW009653, AI284543, AI356264, AI280678, AU153717, AI432851, AI859438, AA741301, AW504168, AI251944, AW975383, AW468349, AU154166, AV749092, AI251034, AA484428, AI364568, BF794808, AV735872, AW023111, BG254947, AI358776, AW732205, AW020891, AI860535, AI354602, BG109444, BF185528, AI381490, BF844773, BF971280, AI254770, AI251203, AW976024, AI417469, AI251284, T08386, BF809775, AI732671, AI961983, AI345334, AI859906, AV740423, AA807704, AI363851, T51556, BE439681, AI928890, BE837822, AW958711, AI754567, AL037927, AI754105, AL042667, AL042670, AI755214, AU133267, AW963599, AW303098, AI246594, AI687972, AW502185, AL047645, AW019964, AW958427, AI250552, BF673849, N33587, AU160445, BF967309, AU159614, T12424, AW064007, H62343, AW341882, AW303872, AA554866, AA609834, BE392753, AA657910, AV738171, AW068853, BF920612, AA604751, AA523695, AW272389, AI866996, AA831638, AW576251, AA057522, AW132097, AL039057, AV755634, AA363957, AF238381.1, AC018766.2, BC001801.1, AC090941.1, AB014085.1, AC004187.1, AP000515.1, AL109963.4, AC011555.5, AK025621.1, Z82195.1, AC004846.2, Z68873.1, AC011526.7, X64467.1, AC006323.3, AL022336.1, AL022318.2, AL139022.4, L35532.1, AC005338.1, AC006529.1, AC018755.3, AL353777.18, AL445928.8, AL353692.14, AL354808.24, AL022313.1, AC005393.1, AC005740.1, AL049312.1, BC009183.1, AF109907.1, Z94865.1, AC023359.26, AL035415.22, AL049282.1, AL031602.14, AC008055.6, AC000134.14, Z84469.1, AL359792.3, AL138881.12, AK022536.1, AL589656.5, AL157365.19, AC067722.21, AL136123.19, AC079754.4, AK023233.1, AC007011.1, AF090925.1, AB045364.1, AL021578.4, AC026398.4, AL031728.12, AC078846.2, AF280899.1, AF283321.1, AC008537.5, AF092858.1, AC005800.1, AL136172.16, AC021068.17, AL136979.16, AC003029.2, AC006071.1, AC007384.3, AC005954.1, AC005779.1, AL133507.8, AC005409.1, AF281936.1, AL133260.12, AC006025.2, AC090509.1, AC090005.1, AC068319.4, AC011442.5, AL133380.5, AC005379.1, AC005594.1, AC004659.1, AC024157.4, AL158836.16, AC015541.21, AC026162.5, AL138968.18, AC008755.6, AC018816.5, AC018494.6, AC006084.1, AC004826.3, AL390061.9, AC004792.1, AL035423.4, AC087072.2, AF254822.1, AC009399.5, AL133548.6, AC006014.2, AL022316.2, AL009172.1, AC006362.2, AC024082.6, AL136231.12, AL356316.18, AC023798.16, Z83844.5, AC011452.6, AC008766.4, AC008750.7, AC005231.2, AP000689.1, AC004241.1, AC008985.6, AC002312.1, AL050307.13, AL034429.1, AL132639.4, AC004257.1, AP002534.1, AL096841.6, AC002551.1, AC008754.8, AC004805.1, AC004019.20, AC068724.7, AC053480.5, Z68870.1, AC012306.11, AC004655.1, AC010521.4, AC008747.5, AK027639.1, AC004263.1, AC005837.1, AL022721.1, AP000130.1, AC064814.7, AL355052.3, AL359753.9, AF288742.1, U91321.1, AC003662.2, AC008102.17, AC073532.18, AC003102.1, AC084865.2, AL008707.1, AL136365.9, U52112.1, AL078638.9, AL078591.18, AL356354.10, AF314058.1, AP000967.2, AC073917.19, AL358133.11, AL138743.5, AC007679.4, AL121992.24, AL513550.9, AL021394.10, AC009475.4, AL109827.8, AC026464.6, AF111168.2, AL121890.34, AC005257.1, AP002815.3, AC002994.2, AL022162.1, AC008543.7, AF200465.1, AC027319.5, AL021453.1, AC011242.8, AB015355.1, AK022032.1, AC004831.1, AC004103.1, AC005844.7, AL353807.18, AC009060.7, AP000359.1, AC009263.6, AL138784.30, AL139008.10, AC006121.1, Z68128.1, AC010168.6, AC007201.1, AC004089.25, AC000159.6, AL139318.9, AC090937.1, AC004686.1, AC002352.1, AL109921.21, AC002404.1, AC026776.4, AF283256.1, D64108.1, AC003966.1, AC010616.5, AL022334.1, AL035071.17, AC015651.18, AC008745.6, Z80232.1, AL121753.30, AL136136.7, AC010679.6, AC011510.7, AL160159.12, AL159997.14, AL450265.11, Z94044.1, AC010083.5, AC004797.1, AC008699.5, AL049747.1, AC005796.1, AC004885.2, AL031662.26, AC011472.7, AL133246.2, AL121989.12, AL355480.22, AC016620.6, AC009481.4, AL135744.4, AL135927.14, AC007227.3, AL159988.12, BC000970.1, AL109920.15. HRDDQ39 188 840405 1-762 15-776 AA564252, AV763026, AV763058, AI499954, AI654738, BF763954, AI066646, AW813668, AI537020, AI801505, AI491765, AI251576, AW502796, AW272294, AA935409, AI040051, AI306232, AA503298, BE062545, AA225406, AI583466, AW274191, AI755202, BF771774, AW962251, AI635028, AV764259, AC008073.4, AC020604.9, U95740.1, AB020867.1, AF001552.1, AL049712.12, AC025168.7, AL512347.14, AC012469.9, AC007066.4, AC002996.1, AP003439.2, AL357752.19, AC073273.9, AC008372.6, AP001883.5, AC004973.1, AC013264.4, AL163285.2, AC073657.5, AC009516.19, AC012284.5, AL031230.1, AC005034.1, AC012476.8, AP002815.3, AC011485.6, AL365338.17, AL160397.17, AL008635.1, AL158830.17, AL033518.14, AC007172.6, AL391065.6, AC005768.17, AC007425.16, AL031123.14, AC005911.6, AC090947.1, AL157838.24, AL591398.2, AC009756.9, AC009274.9, AC006600.4, AC007748.2, AF312915.1, Z99716.4, AC008733.7, Z83822.1, AC004675.1, AL121753.30, AL121754.18, AL109804.41, AC006511.5, AC005157.1, AL133324.13, AC006480.3, AL080243.21, AF088219.1, AC004887.2, AL139353.3, AC002563.1, AC006435.7, AC005081.3, AL160236.4, AC005859.1, AC010651.7, AC022414.6, AC025679.4, AP001752.1, AL442167.1, AC018738.4, AL031685.18, AL352978.6, AC025262.27, AP000557.2, AC012320.6, AL133229.40, AL031311.1, AC008440.8, AC003962.1, AL034372.33, AL133295.16, Z93020.1, AC004209.1, AL078581.11, AC010654.8, AC007226.3, AL356503.18, AP001922.4, AC010789.9, AC018690.5, AF168787.1, AL080314.29, AC011510.7, AE000658.1, AL160492.5, AL133244.1, AL117380.28, AL161629.10, AC010320.9, AC002546.1, AP000692.1, AC011742.3, AC008720.6, AC005023.1, AC025588.1, AC004584.1, AC004848.1, AP001725.1, AF019413.1, AC005013.1, AC011443.6, AL121899.37, AC006449.19, AP001694.1, AL359682.4, AL109825.23, AC034240.4, AP000355.1, AC011473.4, AC008569.6, AC009570.13, AC007381.3, AL365295.4, U91321.1, AC007363.3, AC009502.4, AL157882.5, AC006130.1, AL445201.14, AL137061.12, AL135818.3, AD000092.1, AL121578.1, AL035404.20, AP000513.1, AC069548.4, U91323.1, AC008507.8, AC005747.1, AC005071.2, AC009503.3, AL121653.2, AL359644.10, AL031622.1, AL031659.9, AC004526.1, AC010102.3, AC006270.1, AC021752.5, AC068319.4, AF031078.1, AP003357.2, AC008511.6, AC078846.2, AL445184.11, AC009275.6, AC009194.8, AF030876.1, AC018663.3, Z84474.1, AC008556.5, AC002350.1, AC010543.8, AC003108.1, AC007276.3, AJ003147.1, AC008764.7, AC015982.9, AL049830.3, AF003529.1, AL080239.11, AC020931.5, AC004125.1, AL391827.18, AC010150.3, AC005043.2, AL137222.17, AC011005.7, AC020750.3, AC004859.2, AP000356.1, AF001549.1, Z94801.1, AC005914.1, AL133342.14, AC007308.13, AL355836.3, AC009953.4, AC005138.1, AC008493.4, AC006116.1, AP001052.1, AL122001.32, AL139100.9, AP001732.1, AC009137.6, AL035450.1, AC003037.1, AC006042.2, Z84484.1, AC004089.25, AL357519.19, AC002312.1, AC026368.37, AL449223.7, AL359695.6, AL022159.1, AC009955.4, AF279660.2, AC008616.6, AL139230.25, AC005952.1, AC006443.1, AL121586.31, AC008551.5, AL035367.5, AL133245.2, AL354720.14, AC005740.1, AC023114.5, AC007318.4, AC090951.1, AC066597.4, AC003049.1, AC008821.5, AL162571.9, AC019171.4, AL136162.17, AC022083.6. HRDEX93 189 816046 1-1667 15-1681 AL527900, AL529036, AL529408, AL533906, AL533907, AL529035, AL527941, BE903615, BE791071, BG166982, BE299248, BE793113, BE909498, BF205960, BE900230, BF663336, BE900477, AU138677, BF317122, BE902376, BG105338, AL046917, BG248168, BE387420, AU128036, BF796169, BF674884, BE734698, AW247351, AW245938, BG122744, BF794696, AI832791, AU139448, BE295651, AI310124, AW674400, AI792211, AW515975, BE265061, AW245495, AW675728, BE394504, AA226400, AA569956, BE300693, AW388658, AU150370, AI890679, AW402628, AL527942, AI962952, AI221330, AI245352, AI601125, AW469172, BF957886, W80352, AW188512, AW405360, AI215909, AI564190, AI208267, AA533187, AA633700, N95345, AA431700, AA311285, AA643585, AI865794, BF221803, W26197, BF241479, N90770, AA040058, BE251149, AW512882, AA031577, N30739, AI890616, AA349670, AA994951, AI372503, N59649, H91459, AW731826, AW672782, BE265966, BF807476, AA554209, BF802350, AA226371, AA737167, AW592984, BF802840, AA349671, H72140, AW006451, AA176708, AA037422, BF807473, AI352253, AA972235, AW934951, AI905350, AU158023, T95955, AI733502, AA229521, AA226888, T95961, AA226924, AA323327, BF767741, BF371957, W67484, BE767129, AW247493, T95866, T95860, AL046918, AI148858, AA876362, AA216424, AA936123, BF240778, BF476991, H13591, AA813410, AA173027, C03952, AA641404, N78203, AA865022, AA876167, AI879823, AW518440, BE303017, AI015568, H26512, AI784024, AA040044, W25254, AA431493, AA031456, AI275659, AW513500, AA861578, H54187, N35164, BE770665, R77485, AW088915, AA384005, AA470650, H13222, BF767990, BE241964, R38117, AA368017, W80351, AA336001, BE872227, AA054613, H91107, BE546333, AA054553, BE171388, AI378983, R69693, R38031, W21999, AW749739, AI364635, AI961834, BE242695, AA303798, R57459, AA994783, AW958926, AB026628.1, AB018357.1, BC002773.1, AK001420.1. HRTAP63 190 780698 1-2562 15-2576 AL530903, BF980210, AV713636, AV714538, BF795697, BG165908, BG034785, AW954212, AA476834, AA454040, BE787658, W87846, W95796, AV723163, AA210879, BG121323, AI140750, AA394298, BE544064, BF110177, BG260733, AW957532, AW835225, AV715167, AW043868, W95753, BE675523, AI830085, AV684273, BF669098, AW575257, AI719282, AW402599, AA594596, BF030937, AV751996, AA151651, BF439829, AI972457, AA203350, AW835231, AV698320, AW835223, BF195333, BF245739, AI458367, BF217997, AW103450, AV646999, AA443779, AI804705, AA779750, AA609993, AV646707, AI161426, AA883267, AV761220, AW105020, AI859827, N21490, AA769659, AI961457, AI963269, AV748401, AV702852, AA454948, BF477944, BE378300, BF507584, AA398140, AA829928, AA723665, AA152423, AI066682, C05924, AI342144, AI818909, AI949342, AW173168, H95180, AI150177, AI744274, AI373130, AI936317, BF131934, AW935736, AI373127, BF184877, AW848815, AI168246, AW630390, AA703773, AI809600, AI858227, AI620702, BF211545, AA453622, AW511827, BE550555, BF352641, AI811412, BF216016, AI149376, BF028661, AA777078, AA988774, AA825373, AA745603, AA447847, AI634257, AI148253, BE568959, AW474847, H50762, AW340117, AI148595, AA152318, AA455325, H18773, AA446817, AI983483, N70494, AI950667, AI367305, AA447696, AA165032, BF349702, AA595127, W37577, AI865137, W60533, H27027, AI088311, AA781728, BE244882, AA411860, AI380799, BF130302, AI927370, AA150348, AW876985, R96314, AV726405, AA729374, W32295, AA448492, AI453093, AW769995, W04863, AI263830, AA083837, AA133757, AV734814, H24217, BE564563, N99875, N77905, AA679441, AI352336, AI188487, AI432136, AA033645, AI266690, AI433965, AA877077, AA055324, W44808, H49413, AA411995, AA833544, AI300087, BE972332, AV682350, AA992809, AA814064, AA741027, AV702746, W32538, AA683291, AA621431, AA902136, AA214623, AV647110, AA663647, AA494354, BE245415, AW151578, AW150662, W60562, AA705000, AI950580, N27003, AA345942, H85708, AA133758, AI627657, AA224004, W37452, T80362, AA452695, AI146286, H49227, AW074691, BG142207, H47030, F25806, H85509, BE244420, C17218, H24204, AA480190, AV651579, AI272131, T80478, AI381311, W87586, W37696, H18682, H24218, AV647065, N29206, N28458, AW468405, BF081529, W44802, AA927134, AW821055, BF854323, AA083939, F35729, AA682763, R31829, AA148436, AA125918, H95144, BE246322, W44717, AW194993, AA729762, H50669, AA343940, BE244987, AA115539, R26021, N35260, H46491, AI902181, AI149536, R37220, AA325890, AF151885.1, AK025730.1, BC000836.1, AF135161.1, AB062991.1, AC007298.17, AF172940.1, AC022149.3, R26823, R38842, H88357, H88417, H88357, N40125, W05840, W25309, W32702, AA027857, AA027923, AA034476, AA115050, AA151732. HSAVW42 191 637660 1-581 15-595 AI336192, AI911235, BE644656, AI459354, BF030919, AI333569, AA652155, AW974708, AI700779, AA932386, AI922689, AI888953, AA848053, AI863382, AI932794, AI554821, AI539687, AW081231, AI587156, AW189415, AI610362, AA225339, AI934011, AI498067, AW168373, BG031338, AI280732, AI590423, AI590686, BF724894, BG036614, AV709522, AI242251, AV756150, AI890907, AI687065, AV682074, AI583065, AI472536, BF811793, BF812960, AW167222, AI636588, AI249946, BF970652, AW169234, AI431909, AI610115, BF981148, AI635016, AI874243, BF970768, BF727034, AI798351, AI580254, AI627988, AL037582, AL037602, AW022682, AI916419, AI872804, AW072719, AW151714, AI613038, AI470293, AV704962, AI588892, BF725644, BE965169, AV757161, AA470491, AW172723, AI281867, AL514791, AW983783, AI802542, AV682875, BG256090, AA502794, AI758437, AI609409, AI798456, AI345551, AI628833, AI590830, AI560683, AW198090, BG108070, AV733470, AI591407, AW090071, AI335426, AI348777, AI521244, AW983832, AI955906, AI288050, BE963244, AW084117, BE546262, BE783819, AL514627, AI274541, AI274745, AW059713, AI612913, AI493576, BG165979, BF726207, AW268302, BF033757, BG001235, AW104196, AI538764, AW983754, AI633125, BF726237, R36271, AL042628, AI539771, BG108268, BF528717, BF970263, BE621472, AI680498, AI269696, AV714710, AI655841, AA910956, AI890223, AI921281, AW169039, AI686073, AI583085, AV682224, AW162189, AW105601, AV648430, AV714100, AI567612, AI697372, AI702073, AW827227, BG179993, AI866082, BE018334, BG114304, AI633000, BG112239, AI950664, AL039086, AL046849, AI816947, AW302954, AV734180, AL036980, AV682791, AW169604, AI249877, AW082088, AL041105, AI866770, AI887772, AA427700, AI376180, AW002174, AW089179, BG036846, BE966927, AA807352, AI241923, AW167918, AV755589, AI864836, BE892503, AI621362, AL048323, AL040827, AI570807, AI634345, AL048340, BE785868, AI608932, BE910373, AI537677, AI879064, AW081255, AI738854, AI956080, AL080046, AI440263, AI862135, AI690748, AI865906, BG180295, BF868489, AA833760, BG108309, AI537261, BF342157, BF764528, AI866083, AI623941, AI922315, AI433157, AI870192, AI597731, AA641818, AW198112, AI637584, AI440239, AI345677, AW151729, BF753013, BF924882, AW004886, AW079336, AW983691, BF762612, AI520785, AL119863, BF344691, AW022699, BF814357, AI580694, AI923989, AI499986, BF343568, AW169848, AI627893, AI572717, AV715462, AW301513, AW081298, AA572758, BG109590, AW089310, AI554344, BF752999, BF968017, AW079859, AV656595, BF925729, BG252914, AW301505, AI620093, AW088538, AI538850, AW163834, AL036403, AL389939.1, BC005678.1, AB062942.1, BC008485.1, AK000432.1, AF000145.1, AB047904.1, AL359618.1, AK024538.1, AL133067.1, AL049452.1, AK025798.1, AL389982.1, AK025857.1, AL136844.1, AK027213.1, AB050410.1, AL137476.1, AL122110.1, AL137550.1, AK027182.1, AF090901.1, AK026057.1, AL137648.1, AL137488.1, BC008893.1, AL049382.1, AL512733.1, AB048974.1, AL136747.1, U38847.1, AF230496.1, AF183393.1, AF090900.1, BC006525.1, AL137533.1, AK026532.1, AK025092.1, AF159615.1, S78214.1, S61953.1, AK000614.1, AK026480.1, AL117578.1, AL023657.1, AF061943.1, X72889.1, AL389935.1, AJ299431.1, AF143723.1, U58996.2, AL133557.1, AF056191.1, AF081197.1, AL122123.1, Y16645.1, AK000083.1, AF057300.1, AF057299.1, AL162083.1, AL122049.1, AL137526.1, AB063070.1, AL080159.1, AL137560.1, BC006103.1, AL117460.1, AL080074.1, AK027160.1, AK026592.1, AK000418.1, AF090943.1, AL359583.1, AF217987.1, AB056420.1, AJ242859.1, AL136749.1, AL110171.1, BC008382.1, AL137640.1, Y10936.1, AL137271.1, BC008075.1, AK027204.1, AF113222.1, BC004958.1, AL359601.1, AL583915.1, AL133606.1, AK026593.1, AL050366.1, AK000718.1, AF162270.1, AF026816.2, AK026642.1, Y10080.1, AK026784.1, AB055368.1, AL117435.1, BC008780.1, AF217966.1, BC006440.1, AB047801.1, AL137529.1, BC007680.1, AK027614.1, AK000486.1, AL080148.1, AK026600.1, AL136805.1, X98834.1, AB049892.1, AL080086.1, BC008488.1, BC003627.1, AK000618.1, AL122050.1, BC009310.1, AL110197.1, AB060908.1, AL136789.1, AF090903.1, AL157482.1, AL512765.1, AK000450.1, AL137273.1, AL136845.1, AL133113.1, AL137292.1, AK027116.1, AF285167.1, AB019565.1, AL512719.1, AL359941.1, AK026533.1, BC009026.1, AL136622.1, AL136615.1, AK026045.1, AF225424.1, AL122106.1, AB056421.1, AK025084.1, AK025209.1, AK026741.1, AK027144.1, AK025708.1, AL442072.1, AL117440.1, AL122093.1, AB062978.1, AL137294.1, AK026542.1, AF061573.2, AK025383.1, AL162004.1, AK026534.1, AL162002.1, AB060912.1, AF090934.1, AL512718.1, AB048964.1, AB050418.1, AL512761.1, BC004951.1, AF210052.1, AB048954.1, AK026630.1, AB063084.1, AL133665.1, AL133075.1, AL049465.1, AF061795.1, AF151685.1, AK025254.1, BC007198.1, AL157431.1, AL137527.1, BC003122.1, AY033593.1, AL136882.1, AF207829.1, AF081195.1, X53587.1, AL137276.1, AF271350.1, BC006164.1, U39656.1, AB063008.1, AB050534.1, BC005890.1, AL353957.1, AF177336.1, AK026885.1, L30117.1, AB060903.1, AB060825.1, AB056809.1, AF262032.1, AL359620.1, AK026551.1, AL050393.1, BC007021.1, S76508.1, BC008983.1, BC008387.1, AK027114.1, L19437.2, AK026504.1, BC008070.1, AK025967.1, AK026528.1, BC008284.1, AL136786.1, AL117585.1, U68233.1, AL110221.1, AL162062.1, AL050116.1, AL096744.1, AL133077.1, AL110225.1, BC006807.1, AL050138.1, AJ006417.1, AF106862.1, AL136790.1, BC009341.1, AK026408.1, AL137429.1, BC009033.1, M64349.1, AF097996.1, AL389978.1, Z82022.1, BC006180.1, AB060929.1, AL136843.1, AL133016.1, BC003684.1, AF125948.1, AF090896.1, AB056768.1, AB060214.1, AL117432.1, AL110222.1, AL137521.1, AL137300.1, AL080060.1. HSAWN53 192 634697 1-335 15-349 AA865128, AI174766, AA047715, AW995665, AA702729, AW900503, N74072, AA584450, AW129249, AL079734, AW163293, AV733228, BE313883, AV709273, AA741028, AV733627, AA648990, BE827710, BE172296, AA738097, AL043289, AI250083, AV755512, T08298, AA454041, AV716360, AI147425, AL138228, AA724782, AI921328, AW468297, AL134242, BF832365, N71746, BE968438, AW023265, AI345294, AI732378, AV759518, AI811302, AC078889.20, AC005914.1, Z93930.10, AL390838.26, AC005393.1, AC073145.8, AL355096.4, AL160269.14, AC007465.4, AP001671.1, AF250324.1, AC009509.7, AC004682.1, AC000120.1, AL033523.14, AC025472.3, AC012170.6, AL158830.17, AC006112.2, AC007387.3, AC005670.1, AC004098.1, Z94161.5, AC004531.1, AC015853.8, AC004477.1, AC007036.3, AC019205.4, AC026881.6, AL138823.14, AC020647.9, AC008750.7, AC069277.5, AL050318.13, AC026179.5, AC003024.1, AC024154.2, AC067941.7, AL024498.12, AC006466.3, AL160492.5, AL031055.1, AP000240.1, AL589983.8, AC006204.1, AL359092.14, AL133258.16, AC019046.4, AP000269.1, AL159168.15, AL096701.14, AC002449.1, AP000103.1, Z99570.1, AC006213.1, AP001438.1, AL359538.8, AP000659.4, AL139316.5, AC007488.15, AC023105.7, AC005522.2, AL133320.8, AC011604.10. HSAWZ40 193 634000 1-1005 15-1019 AV730902, BE148579, AW593457, AL120258, AW961858, AW183914, AA724767, AW975579, AA630162, AA715979, BE062935, AW862584, AC007023.3, AC010293.5, AL139326.15, AC024564.4, AC010977.4, AL139095.15, AL118556.4, AC026421.3, AL034410.8, AC015592.6, AL157700.13, AC020637.9, AL445523.11, AL139034.20, AL391139.19, AC017037.10, AL357498.16, AC006343.2, AL512430.14, AC026787.4, AC008685.7, AP003112.1, AL353999.3, AC025765.5, AC003015.1, AP003111.1, AC008664.5, AC006477.3, AC008450.5, AL513328.12, AL023582.1, AL441985.9, AL360270.18, AL354750.12, AL451086.6, AC006928.15, L35657.1, AC012512.7, AL162414.11, AL159159.21, AC004147.1, AL391829.9, AC073542.4, AL391689.1, AP000751.4, AC068802.29, AC007488.15, Z68868.1, AL035424.7, AF044083.1, AL035562.14, AC090946.1, AL392084.6, AC020668.5, AC069462.2, AC007200.1, AL353136.21, AC006515.7, AL136992.22, AL049648.9, AC087070.2, AC087431.2, AL035422.12, AL031965.7, AL031012.1, AC079353.5, AC004021.1, AL035411.27, AC007345.5, AL158192.15, AC007128.2, AP000457.3, AL590426.6, AL391294.16, AC011716.7, AL031312.1, AC010884.10, AC019097.5, U78027.1, AL139112.9, AC003964.1, AF223391.1, AL109800.25, AC009399.5, AL121875.9, AC009753.5, AL356865.19, AC016526.6, AL359643.27, AC011593.8, AL096827.3, AP001669.1, AC005900.1, AP001609.1, AC008905.6, AC006236.1, AC008786.6, AL355052.3, AC010234.5, AL157397.13, AC009476.3, AL583856.6, AC004384.1, AC022419.5, AC008865.3, AC010348.4, AL139327.18, AC073927.9, AL031056.1, AC009501.3, AL096709.11, AL139101.13, AC004932.4, AC008550.4, AL353659.13, AC007179.3, AC026369.21, AC026797.3, AL449189.1, AL157827.17, AC022324.5, AL354831.18, AL353614.9, AL358612.8, AL354948.7, AC005612.1, AL359846.11, AC019227.4, AL357312.8, AC016576.7, AL442167.1, AL136363.4, Z82212.1, AL163285.2, Z83849.1, AL355382.6, AL590225.4, AC010458.5, AL049545.6, AL360232.24, AL512272.15, AC004014.1, AL591770.1, AL137017.9, AL359703.13, Z81311.1, AL158825.12, AC008833.5, AL096793.20, AC020549.4, AC026951.5, Z96074.4, AC010235.6, AC009721.9, AC006957.1, AL137028.9, AC009901.6, AL390027.11, AL021307.1, AL353739.4, AC007656.2, AC023426.29, Z78021.1, AL021997.1, AF095725.1, AP001699.1, AL357774.11, AL023877.1, AF052041.1, AL035078.32, AL357054.14, AC004415.1, AL355596.21, AL109938.8, AL160255.14, AP002791.3, AC040163.3, AL357912.10. HSAYC41 194 688057 1-200 15-214 AF001545, AA548754, AA909788, AW468262, AI751080, AI251827, AA576709, AI800743, AA875953, AW131183, AW149412, AW339554, AI263391, AW168132, BE300485, AI638563, AI920829, AI751079, AV700614, AI682030, BF688845, AA665727, BC008593.1, AC000159.6, AB007864.1. HSDBI90 195 853376 1-1043 15-1057 AU145402, H17256, AI341067, R45451, AW294404, BF593070, AA324600, AA348746, Z40844, AW295349, AK021734.1, AC010285.4, AC026413.5. HSHAX04 196 812178 1-1273 15-1287 AL518245, AL513560, AL518244, AL527318, BE796445, BE729339, BE794797, BE729215, BF570366, BF969527, BE513213, BE797077, BE409736, AV715789, BE729781, BG165883, BF569872, BE730249, BF025786, BF971834, BE747502, BF974060, BF127469, BE394313, AI192460, BE277674, BE387113, BE408890, BF243019, BF685280, BE252479, BE274070, BE386787, BF686552, BE408335, BG179144, BG253243, AI193657, BE383115, BF109402, BE727996, AI978927, BE747511, BE313903, BF027209, BE394458, BG167026, BE387005, BE257613, BE395496, BF127655, AI819133, BE408659, AV701134, BF975755, BE297737, BE276425, BE257900, AW467999, BE409043, BF129135, BE621412, BE251025, BF132821, AV701355, BE736137, BF684777, AA151920, BF205110, AA476567, BE393897, AI589910, BE393107, BE266145, BE390224, BF132684, AA746035, AW406080, BF438288, BE745519, BF238211, BE258291, BE385352, AA224497, BE789268, BF237992, AV701339, AA476450, BE389845, AA922493, AA058904, AV712372, AA809660, AI972258, BE390228, AA031495, AI128546, AA033810, AA934757, AA031586, AI167713, BG111292, BE266333, AV736079, BE294483, BF132501, AI086942, AL513559, AI749671, AA904234, BE410720, AW069373, AA535057, BF835180, BF000188, AA224434, BF591243, AA037753, BF856066, AI189102, AA338222, AI284100, AI198266, BF239384, BF834463, H45086, AI079772, AI620932, W87609, C75448, AI498905, BE621931, AW272369, C75433, H45164, T68206, C75434, AA039244, AW473012, C75456, AA043857, AA627969, AA961372, AW192043, BF759521, AA643805, BE048627, AA916520, AU117291, AA327300, BF836781, AI247228, BF836803, AA480241, AA768298, AI187734, BC004898.1, BC008451.1, AF104012.1, AF042385.1, AF042386.1, AF104013.1, AL049824.4, AL033526.24, T57534, H45163, N79482, W87900. HSKDR27 197 580874 1-748 15-762 AI984221, AI740960, AW015044, BF591015, W80440, AI141908, AA627626, AA969950, AI581286, AW613262, AW170703, AW073992, BF338322, AA480836, R52038, BF436470, AW074677, AA994760, BE219883, AI381244, BE677262, R52037, BE327304, R49984, AW304136, BE042923, R47846, AA359428, AI538725, AW836013, C00374, BE550516, AA887620, AW873686, BG107838, BE048302, H50794, AI961625, W79036, AF177941.1. HSNBM34 198 635131 1-2172 15-2186 AL536186, AL531092, AU122269, AU141256, AL517543, AL536185, BE796661, AI052692, BG253425, BE902706, BG259810, BF343446, BE902245, AU121842, BE256726, AL517542, BG120047, AW149519, AI569076, BG250631, AI683339, BE902473, AU139256, AL513575, AI679283, BE049376, BF219821, AL048381, AI065090, BE867031, BE744360, BE256766, AI935198, AA573792, AI963086, BE250714, AW173560, AI690938, AA573194, AW172834, AW192800, BF570159, AW338466, AW173515, AI871886, AW264055, AW083435, AL513576, AI972125, AV692704, AI569959, BE252221, AW081978, BF569657, BE250299, AI355854, AU137971, AI884543, BF971275, BE279755, AU134876, BG119978, AA553785, AL535675, BG256137, AI624040, AW168911, BE251490, AI983677, BE617477, AA573798, AW770904, AA553547, AW338256, BF569362, AA151761, BE731933, BF914823, AW673207, AW058092, BE378102, BE903055, BF914811, BE328617, AA890369, AW469165, AA614295, BF569993, BE293188, BG024165, AI679858, AA527510, AI954296, AA984269, BG167033, BF972479, BG249971, AW591878, AV698722, BE546239, AU147891, AI826939, AI570855, AA552428, AI905936, AI569573, AL039833, AW250413, BF036826, AI683139, AV693761, AW169566, AL535674, BE962440, AL045941, AA677605, AI336684, BF913847, AW440576, AI205324, AA904129, AI564975, AI755277, BF914809, AI159924, AI521405, AW088700, BE677468, AA912041, AW380632, BF343383, BF341836, AI188483, AA522516, BF220206, AI262223, BE735412, AI361434, BE077394, AA767662, AI635929, BE737090, AU147581, BF993076, AI205326, AI521677, AI811718, BF718768, BE711050, AI460206, AV702376, AI311639, AI719493, BE735537, AV683959, AI521534, BF342262, AI090856, AI699887, AA588032, AA968679, BE350303, AI619645, AU157398, AW674246, AI969109, AA868921, BF915943, AW338122, AA845307, AW246981, BF087911, AA578419, AI888653, AI953992, BE300835, AA629593, AW250183, AI270688, AI000881, AA513481, AI363752, AW105447, AI270679, AI886380, AA812173, AW510415, AA524708, BF340665, AA970400, BF448244, BE219283, AI689550, AI859364, BE467489, AI708506, BE710103, BE256117, AA425828, AA937237, BE970114, F22742, BE544342, AA158179, AA602317, BF914430, AI689542, AA130387, BF973237, AI632858, AA928357, AA127724, AA938081, AW244083, AI682659, AI866898, AI623970, BE710235, BF914962, AI623338, AW073523, AA211741, AW973977, AI358676, F28467, AA643658, R48109, AA151925, BE545049, AA534398, AV705819, AV708856, AW516425, AI860032, BF055758, C06114, BE463647, AA195968, AI370030, BF059039, BE765152, AI581379, R97967, BF001465, AI201086, AW511857, AU135849, BF445756, AI365628, AA128332, BC000399.1, X86556.1, D43682.1, L46590.1, AC003688.1, AF156495.1, D78298.1, D78288.1, D78285.1, D78284.1, D78286.1, D78287.1, D78279.1, D78289.1, D78292.1, D78290.1, D78297.1, D78280.1, D78294.1, D78295.1, D78282.1, D78296.1, D78281.1, D78283.1, AJ012053.1, D78291.1, AF244932.1, T78657, R47994, R87991, R97966, H84516, N26144, W40579, AA002122, AA085935, AA112919, AA128534, AA157448, AA186877, AA192309, AA199682, AA464163, AA464227. HSRFD18 199 840771 1-1875 15-1889 AL037444, BE889424, BF439488, BF446681, AW297772, BE644962, AW295194, BF740081, BF813145, BE466328, AA716418, BE675824, BF196138, AI280149, AA814882, AA813632, BE221432, BE677733, AA358821, BF246362, BF700198, AW452195, AU144490, BE220601, AA761963, AA658222, AA327922, AI123037, AI473112, AW390382, BF992291, BE928864, R99503, AA055144, AU119961, AA182647, AW390381, AU130604, AA182483, AW390436, BF693283, AA054934, BF849246, R98214, AU117739, BF993158, BF002983, AA248903, AA179387, AA182760, AA934941, AI474620, BF670121, BF858341, BE928859, BE150427, AI912621, AA938230, BF919684, AF288393.1, AL096819.17, AK023095.1, AK000945.1, AL117441.1. HSSEF77 200 658725 1-1039 15-1053 AL533175, AL529660, AL529659, AL533335, BG111586, BG032361, AL528013, AI452722, BE837574, AI810976, AW955455, AA887990, AV684580, BE735736, BF309824, BE906705, BF663962, AA719399, AI190326, AI491944, BF976430, AA526699, AI745517, AI291744, AI374991, BF984742, AI828575, AI147212, AI291429, AA971270, BF914316, AI681964, AA747482, AI589781, AI760672, AW973135, AI191377, AW054812, AI282167, BF448406, AI076763, AI382209, AI819092, BE314426, AI653887, AW026209, AI291350, BE144273, AI025483, AW194181, BG032936, AI125991, BE205789, AW005070, AW166142, AI479431, AW340398, AI872247, H14119, BG120898, BF475933, AW001576, AI950052, AI038728, AA781105, AI983727, AI186987, AA635803, AA446939, AA393844, AA393826, AA041546, BE208340, AA595299, AA588205, AA968514, BE905601, AI272049, AA580350, T34621, AI445351, BE910075, AA039492, AI588901, W42714, R43919, AI095816, AA224332, AA635837, AI205639, AA308975, R88071, AI568018, AI261987, AI299347, AI346541, H19688, T67080, AA427787, AA652370, AA618584, N95318, AI133427, H20066, R60201, H19689, AW779512, AA536032, AA308974, R88422, T31859, BE140668, AI690936, BE140651, BE140664, BE140646, BE140650, BE140649, BF343597, BF726607, BE548803, AA953968, BE255716, AW576046, R88070, AA350360, AW178914, AW952572, BG010735, AA069325, AA532555, H52718, AW178907, BF237786, AA362297, BF932320, Z38557, AI372759, AA069378, AW178908, AW178912, AA742707, T31898, BF871214, AA535292, H19728, AI669449, T31864, AI089055, AW178911, R60434, R18809, AI192912, T29995, AA490233, BF871342, AI277302, AA425662, BF971439, AW178906, AA223799, AW973158, BF573284, T85919, AI198749, AW578878, AI336808, N75536, W23910, BF737039, AA375056, AA328758, AW407842, AW439026, AI354778, AI925482, BE394389, AW050516, AW178903, N91860, BG115873, W24575, BE778654, AI281040, W42907, AI028636, AI763001, BF572704, AW172594, AW178913, AA083263, BF093554, AA876195, AV685016, Z42333, AI955663, AA443363, BF922099, W05329, U79457.1, AC005041.2. HSSGJ58 201 747714 1-1940 15-1954 W88633, W88532, AW270778, R07788. HSVBD37 202 637110 1-450 15-464 HSYBI06 203 740766 1-942 15-956 BE785517, BE787741, BG111705, BG033016, BE745842, BE542832, AL041364, BE273298, AV725539, AW957979, AV713687, AV706551, BE612687, AL046322, BF677289, BF381144, BE179216, AA573189, AA581202, BF895251, H22202, AA130055, BE393171, BF589066, AI623423, AI889612, AA147286, BE872822, BE393266, AW750358, AA301758, R15638, AI264187, T61853, AA649148, AA669816, AA374929, BE748901, AA085863, H82057, H54292, AI360690, AW081194, BF847563, AI541147, AA642174, AA864575, AA380599, AA806762, AI932902, AW194802, AA348055, BE783212, AA078084, AI886434, BF674802, BE378761, BF989809, BF977908, AL041450, AW804415, AW955451, BE962907, BF816723, AA551509, BF185308, AV719846, N66945, BF740940, AA601492, AA327572, BE542021, AV709064, AA593060, H56721, BF762046, BF725131, AW157326, BF574125, AA323547, R29012, AV764386, AA669961, AI082510, AI446638, AI064952, BF680940, AI291823, AA984543, BF037677, AI312790, C05755, AI039809, AI336054, BF802386, BF529775, C06327, AI355587, AW977134, AW673941, AA558145, AW327960, AW327961, AI926846, AA360260, AI689256, BG121085, AV734583, BG056233, BG059938, AA714337, AI345161, BE385456, BF995557, N43757, BG056088, AI886365, BF668079, AA450199, BF982646, AA344959, AA723017, AW580735, AI921649, AV709707, AW903691, AI376100, BF438574, AW664161, BE221335, N26276, AW074059, BF826066, AI356904, AI922654, AI564284, AI244254, BE143666, AI678392, AW274064, AW020340, W07032, BF964995, BF574109, BE276559, BF849315, BF975014, R65801, T61559, F31799, AA192337, BF084762, AA384502, BF155030, AI926366, AW971960, AW438916, Z30128, BF155049, H25562, AI547286, AW503446, BF985073, AI053465, BF700500, AL157529, AI923140, N23643, AL049795.20, AK000724.1, AL078584.17, AC002319.1, AC020663.1, AL356421.10, AL354707.17, AL139351.37, AC012405.5, AL162417.22, AC009530.5, AC004934.1, AL513131.1, AC008502.7, K02924.1, AC078992.22, AP000744.4, AL117258.4, AL031286.1, AC009510.9, AC000087.2, Z83846.1, AL136059.2, AC004168.2, AL049796.28, AC004386.1, AL139322.13, AL354977.10, AL357519.19, AL161771.17, AL590638.6, AC006205.7, AC073657.5, Z84478.1, AL034346.31, AC074142.3, AP000298.1, AP000044.1, AP000112.1, AC008249.14, AC002985.1, AC005197.1, AC009412.6, AC007277.2, AC013526.6, Z86062.1, AC004019.20, AC022013.3, AC073347.3, AC009506.5, AC004821.3, AL392106.4, AC005625.1, AL121828.17, AL445071.14, AL157382.14, AL050342.42, AC005005.1, AC007182.3, AL049829.4, AB050050.1, AL357117.20, AL121891.22, AL354696.11, AC002094.1, AL513472.9, AL160408.24, AL035249.6, AL157817.13, AB023052.1, AC006138.1, AP000513.1, AL360020.15, AC007546.5, AL133355.12, AC005391.1, AL354861.11, AC010291.5, AC004253.1, AL034548.25, AF129075.2, AL354984.17, M33940.1, AC074338.1, AL135818.3, AL354995.13, AC006198.1, AC008440.8, AC024576.5, AC008964.6, AC011471.6, AC005548.1, AC008394.3, AL157911.4, AC007676.19, AJ312686.1, AC006994.4, AC000360.35, AL121889.8, AL161629.10, AL161628.9, AC007055.3, AB008502.1, AC007011.1, AL354871.12, AL138812.13, AL353812.13, AL136381.12, AC023347.8, AC005243.1, AJ289880.1, AC018801.4, AL353701.15, AC005330.2, AC002117.1, AC006409.2, AC005914.1, AC007179.3, AL133215.16, AL157837.10, AC005669.1, Z83843.1, AF039907.1, AC079127.28, AL096703.14, AL117350.12, AL158844.14, AC005737.1, AC008969.5, M84371.1, AL136537.4, AP000965.2, AC005866.3, AC007541.9, AL161731.20, AL136325.6, AC004477.1, AL078611.1, AC005221.1, Z82170.1, AL139182.24, AC004655.1, AC010378.6, AC003029.2, AL354808.24, AL157912.5, AL034405.16, AC007619.22, AL441883.11, AP001634.1, Z94801.1, AL161439.15, AC005392.1, AC002992.1, AL121965.19, AL033522.1, AC006057.5, AC005998.3, AL049636.22, AC008663.6, AL109935.39, AL354815.10, AL035450.1, AC016601.6, AC005231.2, Z84467.1, AP000321.1, AC004234.1, AC005704.1, AP000121.1, AL109807.16, Z98742.5, AL354831.18, AC016138.8, AC006028.3, AK024351.1, AL031846.2, AL049565.3, AC008753.8, AC024571.4, AL109806.22, AC005211.1, AP001709.1, AC004948.2, AL590037.7, AC002310.1, AL359713.25, AC010583.5, AC007312.1, AC008764.7, AC016605.5, AL021394.10, AC018682.4, AC008917.6, AL390135.1, AL391001.12, AC002526.1, AC022150.5, AC027644.9, AL136962.19, AL160175.5, AP000244.1, AL157776.15, AC008069.3, AP001716.1, AC001643.1, AC009318.11, AL133507.8, AL132718.5, AC012070.7, AC008997.5, AL121601.13, AC006254.10, AL352978.6, AL138997.18, AL590043.7, X03272.1, AC007246.3, AL132712.4, AL022163.1, AL158203.12, AP000455.4, AC011816.17, AF200923.2, AC005390.1, AP000349.1, AL355480.22, AP000620.4, AL356095.11, AP000742.4, AP002980.2, AL512506.8, AC007250.2, AL136365.9, AC010326.6, AC004531.1, AL445590.4, AL034349.3. HT4FV41 204 853400 1-1750 15-1764 AL515980, BF342485, BG024242, BE392890, BF027674, BF971316, BE298983, BE793618, BF001942, BF970981, AI760358, AI936900, BF001764, AI936213, AI972421, AI660472, AI685616, BF111876, AI589580, BF438674, AI352548, AI806167, AW001510, AI700727, AA602596, AI589071, BE502182, AW515689, AA526910, AI654874, AA854945, AA464374, AI361704, AL515199, AI742777, AI936806, AA308365, AA406024, AA480282, AI669893, AA489645, AI360290, AW772255, AI360045, BF794999, AA406023, AA427779, AW009207, BE999959, R54865, AA877768, AI224523, BF000485, AI760865, AI493484, AW080629, R54856, AI652849, BF738473, AI417480, AA781143, AI123060, D61114, AA622333, BE501244, AA781079, AA489750, AW845472, AA464263, R35409, AI672795, BF588552, BE501931, AW594675, AI025454, F08867, AW340176, AA349747, AI560405, R49206, AW009575, U46337, AA515576, AA443535, AA481437, F11201, AA558995, AW274968, BE892692, BF529100, BE908581, AI479915, AW235302, AW951943, BF032318, AW167825, AI382003, AW026765, BF769982, AW438845, AA318575, AI417016, AI589752, AI679614, AW674472, BG254199, AI926919, AI630739, AW080536, AI658574, AI640408, AI085905, AI917892, R50973, AI951291, AI761329, AW198163, AI932976, AW515657, AA228848, AL515981, AI867349, BF514311, AI627215, AW770041, AI363926, BE313294, AC011547.4, AC005331.1, AL136567.1, BC003076.1, BC007275.1, AL365369.1, BC008920.1. HT5GR59 205 801930 1-1729 15-1743 AI828929, AW293979, AI523779, AA936619, AW450260, AA133205, AA133189, AW368883, AI300320, AI087057, AA725865, AI242492, AA908905, AA864400, AA151624, AW075803, AA381038, AA381029, AA380752, AW075797, AI826859, AF034970.1. HTDAA78 206 566861 1-811 15-825 AV647189, AA326049, AL038602, AL036785, AA370470, F13152, AA350749, BE242772, AW672833, BE969897, AW962768, AU135142, BF701130, AU139947, BE893974, AI752229, AU136362, AU134961, AU139203, AL516351, BF182676, AU134839, AU118483, AU139729, AU140089, AU137541, AU135872, AU120600, AU117568, AU141398, AA095436, BF691608, AU121384, AL519083, BG114606, BG180075, AU116841, BE564255, C14161, AU137009, AW402207, AU120665, AU134088, AU135815, AW401697, BF795970, BG253254, BF130890, AU128710, BE276857, AW402905, AV742153, AA442195, AU135249, AU139670, AU134411, AU135522, BG177368, BE882210, AL537107, AU138561, AL035786, BF903145, AI752757, BF725287, AU134816, AA295005, BE896797, BF792619, AA376087, BE565863, BF106248, BF382779, BG169843, BE882021, BF795672, BE897424, AU140036, BF217892, AV702812, T19262, BF103674, W07391, BG167199, BG121253, Z42435, BF795574, BE730523, BE782289, BE885306, BF208276, BE961165, BE960840, D81404, AA093867, T83204, N55664, AA155940, AU076513, AW836346, AA319776, R98163, BF901489, BF352223, AL137800.12, AF006088.1, AF017807.1. HTEAG62 207 812332 1-2207 15-2221 AA789205, AI077497, AL138197, AI670821, AW628925, BE176789, BF679705, AW117287, AW958637, BE176843, AW369323, W37916, AA608906, AA827227, AA600253, AI160796, AA724269, AA278680, AA292636, AI990171, AA421368, AA421286, AA844108, AA292637, AA768446, W37874, AV692981, AA917528, AA278688, AA303058, AA625767, BE176924, AA382777, BF063207, BE176960, AI972100, BE245143, AA298808, AW316905, H47785, BE299050, BE245089, AA625768, BE843867, BE843864, AF117210.1. HTECB02 208 806305 1-1648 15-1662 BE379373, BG031015, AW149498, AL044040, BG031282, BE857201, BF726235, BF364900, AW959703, AI553977, BF928562, AW612861, BF000820, BF058081, AI817068, AA613730, AI022220, BE830386, AA431887, AI961535, W88594, F25178, AA838686, AI672702, AI333482, AI923896, AA402952, F36762, BE837829, BE717758, W78098, AI400106, AV660436, BE837766, AA535716, BF057504, BE837678, BF928572, BE830460, AA993708, AW027743, BE717863, R78236, AA085673, AA196288, BE837630, BE717820, BE717802, AW237368, F36061, BE837626, BE726105, F29210, W89094, T23988, AI263573, W79153, AI830608, T33297, AI914597, AA857862, AA262845, BE837738, T33694, BE837804, BF931745, AW028769, AA112222, BE830553, F33601, H26531, BE830491, BE830511, T08942, H14458, AA360060, AI300053, AI275634, BF842293, AA374366, AA431886, AA397396, BF439691, BE830471, AI660790, AA687775, BE837644, H86606, AA344590, BF795270, AI868936, AI554895, BE827734, AW977785, T33693, AI758641, AA196161, AA558873, AA837188, AI492169, F24809, BF093769, T24062, BF966806, BE827742, AA025595, AW575651, R84696, AI752555, BE247634, F34286, C21165, AA811094, BE717789, AW025207, BE830540, AW844221, BG026269, AF353674.1, BC006414.1, AF173358.1, AF111170.3, AF086420.1. HTEDJ28 209 762845 1-1233 15-1247 BE677232, BF061401, AW292792, AI581168, AA877125, AW440444, BE349436, AA071509, AA868903, BF732240, BF940844, AI921783, AI342109, AI088444, AI969667, AU144786, AI743896, BG057687, AI264619, AU160612, AW613291, AA071344, AU146005, AI026905, AA609802, AA010635, AA236218, W47649, AU149858, AW103817, AA548757, AL046684, AI215128, AI131520, N25329, AI005190, AI301854, AI244936, AI186155, AI935066, N23317, AA732795, AW148863, AI224009, AA694553, AI382106, W69782, AI078650, AA769526, AA969431, AI282266, C06495, AW592247, AA234139, AL527621, AW390160, AA083834, AA864608, BG168896, AI491973, AA211121, AI797758, AI339980, BE348868, AA707519, AA442229, N45501, N78901, AI139186, W05352, AI144536, AA442894, AA961494, AI074988, AI246446, AI392658, AW183376, AA768697, F33077, AA484612, AA452819, AI130902, AI352222, AA506594, AL517938, T65403, AW377143, AA045703, AA977428, AA431202, R60581, AL518014, AA702219, AW886890, AA056459, AI239789, AW295723, BE005894, AI537842, N21105, N90303, F09614, AI092082, T27964, AW021757, BE673087, D55099, AV702429, R46091, R43333, AA669902, N72031, AA280650, AI818000, AI254234, BE825634, W44412, BE833373, AW884539, AI538078, N80058, AA722648, AI674250, R43151, BF447167, BF222134, AA524771, AW518792, AI799830, AA836174, AI658972, AA725477, W19473, AW392973, AA431526, W47648, AW869322, AA282028, AI718283, W45674, N99484, BF820635, H94760, AI359395, L10413.1, AL138680.15. HTEHU59 210 840385 1-1509 15-1523 BG249175, AL046260, AW963943, AI828967, AW955696, AI760208, AW297718, AI032354, AA417102, AL121147, AA806454, BF216179, AW514160, AA417206, W73366, N39447, N75616, N22370, W73427, N65972, AI370121, AI440453, C16433, AW470432, N98313, AW204089, AA444140, AL046261, H06227, AI796882, AA443958, AA789252, AI221678, AA716720, AW439530, AW873326, AI143241, N35303, AW613664, AA887889, AA845989, AW665345, BE218168, AI333474, AI333483, AI361785, BE464766, BE326250, AI680844, AA936826, BE348681, N94234, T90568, AI693650, AI971432, AI864735, R32990, AA379582, R40841, AA037360, R79419, AA364460, AW502585, T26572, BF248365, R79420, AA765052, BE763303, AV710415, AW137034, BF916703, N48559, BE504072, AW500077, AA663027, H38490, BE545425, AA953152, AI963960, BE907434, AL049814.6, AL137010.4. HTEJD29 211 695798 1-1310 15-1324 BE671326. HTEKM46 212 862069 1-2102 15-2116 AI207971, AI205594, AA682764, AA682743. HTENR63 213 877952 1-1577 15-1591 AL514834, AL519774, AL519775, AV718320, BG250554, BF977554, BE789757, AV756237, BF671459, BG106414, AV715861, BF572599, BG057663, BF217559, AV749968, AI077492, BF184114, AW967760, AA846408, AA459210, AA903217, AI347959, AI582241, AW971593, AI278012, AA100876, AI074700, AI298343, AI074060, AI311669, BF238802, BG119710, AA406286, AI033923, AA724520, AI763007, AI740717, AA128558, AI379680, AA004836, AA833531, AI278000, AI439855, AI400336, AI290630, AA634213, AW150186, BE568250, AA421978, AA128559, AI374862, N25943, N77531, AI023705, N57673, AI056028, H15660, AI335324, AW959305, H81498, R43996, AI350653, AI373175, AV658593, AA814728, AA662834, AA081891, AW955532, H19112, H19113, AV756519, AV733082, W05362, N99540, W31289, AV758671, AI247545, H47163, AI248038, W07017, H47079, Z42635, H52184, N80057, Z40369, AI279669, F02139, BF724942, AA252585, T34459, H52183, F01223, AA004960, F01768, H01616, AA463663, N77397, BE001644, Z44438, N71498, BF590848, H01510, AA082578, N39281, Z28427, AW511477, AA252535, AI378080, F05502, BG169062, AW023590, AW983703, AW983691, BG105812, BG120816, BG026746, BG031815, AL079963, BG179993, AI491852, BF816037, BG029053, AL045774, AI923989, BG121959, AI698391, AV757996, BF343205, BF344652, AW198075, AI815855, BG029829, AV756560, BF793176, BF885081, BG026447, BG110517, AI307604, BF341801, BF338002, BE789764, BF971336, BE964614, AI468872, BF344734, AI699865, BE964497, BG112718, BF970449, BG259944, BE879906, BF814527, BE047737, BG180996, AL119791, AL513907, AV682740, BF969228, AI334450, BF792961, AV733397, BG170937, AI917963, BF527014, AL514627, BF970652, AV716358, BF982767, AL041150, BF895953, AL047275, F27788, AL041772, AL039086, AI358213, BE048026, AL041220, AI802542, AW172723, AI702073, AL043975, BG058150, BG108324, BF970768, BG110946, BE047852, Z99428, AL036638, BE964603, AI537677, AV723204, AW961463, BE879612, BE886858, AL121365, BF812431, BG113188, AI345180, AV723062, AI866465, AV729934, AV714085, BG260037, BF856052, AL119863, BE965067, BG029667, AI521012, BE910373, AV723772, AW269098, AI345148, AI632408, BF037484, AV755207, AW268251, BE965599, BG251478, AL514691, AI824576, AW029611, AW827103, AW151136, BF885675, AW268220, AW149925, AW161156, AL037454, BE874133, BF814357, BG111377, BF054789, AW071417, BF827575, AW079572, AW268768, BE045182, AW983829, AW983832, BG257535, AV755459, AW022682, AV722478, AV724569, BG107576, BE785868, AA640779, AW163823, AL047344, AF242524.1, AL512746.1, AL096744.1, AL117435.1, AL133568.1, AL512719.1, AL512765.1, AL122118.1, AK026592.1, AL122110.1, AK027096.1, AK026506.1, AF104032.1, AB063070.1, AL136844.1, AB055361.1, AL050116.1, AF125948.1, AL133606.1, AL050277.1, AL136749.1, AL512750.1, AL162006.1, S78214.1, AK024538.1, U39656.1, AB048975.1, AK000323.1, AL117457.1, BC008387.1, AF210052.1, AB063088.1, AK026927.1, AL136787.1, AK026528.1, AK026480.1, AL389939.1, AB052200.1, AF260566.1, BC006195.1, AL359622.1, AK025967.1, AB056420.1, AK026613.1, AF090900.1, AL137273.1, AL137429.1, AK027081.1, AL133080.1, AK026762.1, AK025798.1, AL512718.1, AK024588.1, AB055374.1, AL049314.1, AB048953.1, AL122093.1, AL133560.1, AF100781.1, AF090934.1, BC001967.1, BC004958.1, AF217991.1, AF146568.1, AL137527.1, AF132676.1, AF061836.1, BC003682.1, AK027116.1, AL512689.1, AB060839.1, AK025465.1, AL133565.1, BC005858.1, BC008280.1, AK025084.1, AB063046.1, AL137459.1, BC002697.1, AF056191.1, BC007199.1, BC008365.1, AL359596.1, AK026408.1, AL122050.1, AJ299431.1, AK026542.1, AK026045.1, AF113222.1, AL359601.1, AF090903.1, AL353956.1, AK000618.1, BC003683.1, AB052191.1, AL137557.1, AK025209.1, AB060908.1, AL136586.1, AL080148.1, AF106862.1, S61953.1, AK026086.1, AF097996.1, AL049283.1, AF225424.1, AK026744.1, AK025092.1, AL137480.1, AF252872.1, AL133113.1, AL050393.1, U42766.1, AL122121.1, AF111112.1, AB050510.1, AK027114.1, AK024992.1, Y16645.1, AB060826.1, AL136622.1, AL390154.1, AB047904.1, AB060863.1, AB060916.1, AB048974.1, BC003687.1, AB049758.1, AK025383.1, BC004925.1, AL136843.1, AB063079.1, AF090896.1, AK026532.1, AK000718.1, AL137521.1, BC008488.1, AK026865.1, AK000614.1, AF348209.1, AL353625.5, AL133067.1, AB055315.1, AL137478.1, AK025339.1, U58996.2, AL110221.1, BC007021.1, X98834.1, AL137476.1, AL162002.1, AL162083.1, AL050024.1, AK000137.1, AK026784.1, AL137538.1, AL136789.1, AK026534.1, AK024524.1, AL133104.1, BC009033.1, AF090943.1, AL512684.1, AL049382.1, AL133640.1, X69819.1, AL359583.1, AK026741.1, AL512733.1, AB048954.1, AK026630.1, AB060825.1, AB060852.1, AB056809.1, AL162062.1, AK026452.1, AF111847.1, AL110222.1, AK000652.1, AK026464.1, AK026504.1, AL110196.1, AK000445.1, AK026583.1, AK000647.1, BC008417.1, AL137550.1, AL512754.1, AK025958.1, AK025414.1, AK027204.1, BC006807.1, AB055303.1, AB060887.1, Y14314.1, AK025312.1, AL050149.1, AL133016.1, BC003684.1, AK025772.1, AL442072.1, AL353940.1, AL110225.1, U91329.1, AK027868.1, AF078844.1, AF091084.1, AL080159.1, AL137271.1, AB047941.1, Z82022.1, AK027193.1, AK000083.1, BC002733.1, AK026647.1, AL137488.1, AL136892.1, BC006201.1, AF321617.1, AF026816.2, AK026533.1, AK027113.1, AL049466.1, AL137526.1, AK026526.1, AL049430.1, AL137560.1, AB063008.1, AF217987.1, AK027164.1, BC009212.1, AB062938.1, AK025632.1, AY034001.1, AF061795.1, AF151685.1, BC004556.1, AF090901.1, AL389982.1, AL080124.1, AL080060.1, AB060912.1, X82434.1, AK026353.1, BC008899.1, AK000432.1, AF218014.1, AB047615.1, AK026959.1, BC004951.1. HTGBK95 214 834490 1-1117 15-1131 AL522125, AL522126, AL519350, AL529333, BF978108, BE217821, AW299468, BG106602, BE326803, AU149173, BE646271, AU153293, AU154281, AI432448, AI039818, BE467032, BE042910, AU152129, AU160794, AU153911, AI571337, AA237091, AI963695, AI635374, AA932292, AW043706, AI302679, AA236679, AA767544, AI735388, N42646, AI590210, AI224546, AI632813, AA234900, BF338277, AI085872, AW002721, AI049665, AU149933, AI142800, AI269171, AW242940, AI741857, BF034584, AI653576, R94321, N68116, AA513076, R43971, R94225, H05324, H24266, BG111524, R97540, Z41226, AA235171, N67392, AA991730, BF925392, AI521589, BF966823, BG110768, AW410784, BE205895, AI914747, AV699173, AV752994, BF037819, AL046227, AP001728.1, AP000010.2, AP001432.1, AP000151.1, D87343.1, AC007383.4, AP000344.1, AC007172.6, AL021155.1, AC011481.4, AC006994.4, AL591104.2, AC011491.5, AC002565.1, AC002073.1, AP000030.1, AL512347.14, AC018639.8, AC010092.4, AL391241.21, AC004638.1, AL136168.4, AC084865.2, AP001746.1, BC008280.1, AL354760.11, AL132768.15, AL035458.35, AL365338.17, AP001711.1, AK025798.1, AC009779.18, AC015982.9, AL031726.22, AL049539.21, AC004797.1, AC034240.4, AP000208.1, AP000130.1, AL031733.3, AP000247.1, AC083871.2, AC083884.6, AF042090.1, AC018719.4, AC006334.3, AC011811.42, AC007563.2, AC004878.2, AC004227.1, AC020552.4, AP000045.1, AP000113.1, AL118520.26, AC008551.5, AC018758.2, AL163282.2, AL353716.18, AL157372.18, AL590037.7, AP001710.1, Z82214.23, AC008507.8, AC023880.5, AC020928.6, AC008755.6, AL356747.18, AL445645.10, AL031727.42, AC005562.1, AC002425.1, AL079342.17, AL136126.34, AC004883.2, AL034374.2, AC019184.3, AC009501.3, AC002558.1, AC006435.7, AC004383.1, AL031985.10, AC073316.6, BC007199.1, AF307337.1, AL133444.4, AC011484.4, AP000313.1, AC007551.1, AC011450.4, AC006023.2, AL158158.14, AL121897.32, AF334404.1, AC006006.2, AC007003.4, AL050307.13, AC009484.3, AL391122.9, AC007597.3, AC005086.2, AC022425.6, AC006039.2, AP001695.1, AC073964.3, AC006345.4, AC009220.10, AC004166.12, AP000050.1, AJ400877.1, AC005399.19, AL137060.13, AC004750.1, AC025754.4, AC003043.1, AC004882.2, AC024028.10, AL022165.1, AL121722.9, AC005212.1, AC005736.1, AL022311.5, AL035423.4, AC079602.15, AC010650.8, AC004098.1, AC006487.8, AC012306.11, AP000117.1. HTGGM44 215 842856 1-3002 15-3016 AW974580, BE764084, AA651951, W01997, H68969, AI459019, H70945, AA486949, T66948, T66949, AA486772, BF329143, BF108414, AW469166, AI568694, T57664, AL133623.1. HTHBZ06 216 832477 1-609 15-623 BG107523, BG180234, BF668800, AL514985, BF339863, AI400160, AI566873, BE909457, AW262875, BE906621, AW470063, AI758577, BE907206, AA777509, AV715444, AW131846, AA406614, AW087747, AI811951, AI371781, AI742506, AI337891, BE738291, AA934901, N40173, AW157527, AI742505, AI374781, AI081113, AW173107, AI379523, AV756830, AI139790, AA195689, AI801399, BG054839, AA532727, AA235284, AI087379, AI792601, AI952545, AI245243, BG026067, AI805770, AA600140, AI040546, AV703045, AI753737, AA625963, AW591860, AA159931, AA477326, AI360032, N40209, AI864174, BF197737, AA430365, AI829158, AI869836, AI955815, AI804015, BF909529, N30689, AA478600, C16344, BE906555, AI640196, AW072764, BF306291, AA905154, AA481723, AA758776, AI371005, R78607, BE783860, AA865424, AW242058, AI185821, H64413, AA302463, H64463, C16267, C15288, AV750104, H92638, AW972807, AI566669, AA302462, AI468749, AW090440, AI336687, AI934133, AW512971, BF542108, C16184, C16080, R78608, F05286, AI269595, AW800298, AA021044, C16548, AA315033, R46768, R35721, BE885010, BF870311, R25875, F02653, BF675020, AA761420, F22486, D57610, F00189, AA906821, BF028115, BF081348, AW367390, BE465797, Z24901, AW963734, C16270, AA527113, AA527036, AA373921, BE074601, AA479641, BE074603, AI680768, AW316622, AW606067, AW606056, AW370132, BF766618, C16603, C16455, C16334, AI273095, AA833555, AA479334, AA657967, AV748779, BE737983, AW972454, AI857650, BE925004, D11915, AA479335, D12263, AA165042, BF379271, BF087468, H89161, BF743712, AA732498, AV646354, D12285, AW954020, AW085952, AL514986, AA363869, AV736361, D12284, AA989012, AF006484.1, AB006077.1, AC010904.10, AL139184.8. HTLBT80 217 840045 1-2087 15-2101 AL519674, AL518564, AL530114, AL524125, AL518563, AL524124, AL519673, BG119582, BE736220, BE734743, BE782619, BF795936, BG248163, BE869185, BE893350, BF435225, BE905414, BG026633, BF033083, BF970046, BE885230, BF692625, BF692541, BE892741, BE393898, BE389940, BG163906, BE313920, BE312030, AI741613, AI762578, AI241474, AI813813, AI922418, AI990378, AA018345, AW631237, AW151233, AI400794, AI420163, BE550276, AI949071, AW963076, AI922430, AA614565, AW051437, AA018346, AA612852, AI000311, AI338519, AI360869, AW613433, AI356485, AW590872, W56183, AA417581, AI214800, AI671156, AA451942, BE242648, AW390145, AA001019, R69763, AI419907, AA768838, AA482598, AI696492, AW473585, AI674961, BE868575, AI247090, H08477, AA576510, BE391031, H06603, AI018102, T56902, W56260, BF372172, AA001020, AI285366, R87304, BF928779, BG152437, AA814595, AI569050, AI239612, H06633, AI623626, R69764, AA971138, H07140, BE856299, AI357631, AI001995, AW243905, R48323, BF003017, H43938, H52166, AA026966, BF988194, W22979, BF372164, H89737, R87305, BF677308, R48432, AA347636, AW080561, AA593837, AI459770, T56903, H08759, AW750152, AA876261, AA450330, AW797547, BF508949, BE833483, BF512980, AW300516, BE076134, AA514688, AI476002, AW884714, BF992680, AI568120, AA578364, H89800, BE503792, AA344443, T77366, BF811395, AV699752, BF748071, AW367168, AA450329, BE833631, AW198236, R30662, BG115081, BG115274, AW275152, AA216315, AW821860, AA347637, AW953095, BF088397, AF132949.1, AL133227.15, Z55376.1, Z55375.1. HTLCX82 218 847091 1-906 15-920 BE895266, AI692666, AW157552, AI015973, AI689900, AW963262, AW131853, BE218199, AA894904, AI758863, AA778702, BF437932, AA808247, AI990148, AI692715, AI472271, AW001076, AI369125, AI366347, AW172292, BE218953, AL042649, AW663918, AW592717, BF197398, AI671343, AI689434, BE327560, AA705479, AI890951, BG056326, AI986066, AA884562, AA443162, AI457884, AI824337, AW613722, AW249607, AW245434, AA635189, AW295998, AW016141, AW884250, AA127947, AI339109, AI205715, AI983135, AW167189, AI651614, BF115478, AI655941, AW339846, AA576928, F34913, BF195244, R44195, AW615232, C17097, Z38497, AA127981, AI674340, BG179291, AA371600, BE407998, AI857515, BG057320, AI954654, H55670, AA913215, AA463452, AI968885, AI636240, BC003015.1, AC004471.2, L77570.1, L77566.1, L42347.1, U84520.1. HTLDU78 219 637702 1-1304 15-1318 AA417099, AA435761, AA417203, BF748721, AA972917, AI660387, BF748720, AC011444.5. HTLEV48 220 723799 1-1056 15-1070 BG113122, BE246780, F21473, Z18867, T48103, BE246456, F27546, AL079300.11, AB042648.2. HTLFA13 221 535937 1-1146 15-1160 AA599080, AC018808.4, AC034193.4, AC022007.3, AC090958.1, AC018841.3, AC022234.3, AC007999.12, AC018828.3, AC018758.2, AF168787.1, U91321.1, AC002091.1, AC010530.7, AC004765.2, AL031427.15, AF111168.2, AC005911.6, AC021188.6, AC005783.1, AC010150.3, AC078962.30, AC024028.10, AL121585.22, AL049795.20, AL391834.8, AC005829.1, AL353579.17, AC022384.4, AL049776.3, AC007030.3, AL096700.14, AC002352.1, AC008011.11, AL158830.17, AC006130.1, AL139329.15, AC018500.3, AC005077.5, AL136137.15, AL022315.1, Z85996.1, AP001752.1, AC025165.27, AC006449.19, AC009144.5, Y18000.1, AC005056.2, AC006211.1, U95742.1, AC010956.12, AL117381.32, AC008162.3, AC022392.4, AL137244.28, AL050335.32, AC011247.10, AC005095.2, AL121601.13, AC005531.1, AC074121.16, AC004491.1, AL049780.4, AL035704.9, AC010422.7, AC018812.5, AC007707.13, AC018644.6, AC008806.4, AL023583.25, AL031985.10, AC018663.3, AC005529.7, AC008755.6, AF190464.1. HTLGI89 222 835069 1-2363 15-2377 AL527649, AL521837, AL521838, AL526812, AL522637, AL516967, BE796246, AL516968, BE733427, AW953470, BE267273, BF984794, BF663431, BE746021, BE744871, BE727677, BE792949, BE891911, BG032127, BE732800, BE880158, BG029699, BF739970, BE547454, BF033906, BF341854, BE410292, BE407731, BF974054, BE730406, BE280141, BE276759, BE396111, BG033296, BE313127, BE266155, BE276474, AW245780, AW245421, BF726872, BG259961, AW170348, AA454052, BE387107, AI125210, BF888054, AW960189, BF109831, BE883630, BE207211, BG024467, AW403899, BF894254, AA789053, AI208601, BF432565, AA031930, AA032048, AI024666, W07699, AW615502, BE296793, AI001138, AI200867, AI356072, AA622587, AA632148, AA934612, AI369198, AI570447, AA846843, AA758922, BF907531, AI332639, BE276249, BE386995, BE795828, AW271396, AI095065, AI208972, N62476, C06239, AA864754, AI278658, AA431596, AA676722, AW402977, AA099581, BF888062, AI125001, AA609502, BE901965, BE901394, BE797702, BF110024, BE902040, R87506, AI570705, AA847774, AA062669, AI283903, H80426, AI493468, AA351375, AA766390, AA621386, AU141193, AA468656, AL522636, AW960190, AW387425, AA813039, BE733825, H24175, AA361930, AI862627, AA305197, R98946, BE304538, AA975165, N80670, BE019577, AA644232, BE736900, AI034164, AW245820, R23321, AI245639, R78483, BE265415, AW375225, BE266374, BE280632, AA137081, BE733565, BE901113, AW955959, AW375213, BE267493, AW375220, BE539912, R23244, BE733342, N79196, T16377, T09166, BE799665, BG222879, M85399, R98861, AW080224, AA628355, W73606, AI763081, N50148, AI721021, AW089049, AA226886, AW615653, BE464923, AW089305, AI004405, R87588, T04952, R10049, AW078905, AW083608, H17382, BG223318, AA811085, AI245727, AA380030, R78526, H80425, AA226922, AW371367, AW732928, BF931203, R10928, AA136972, AW377690, AW374893, BE841909, R10879, AA353058, AW374895, AA995577, AI001882, AI015767, AW363526, AA377815, H24067, BG223317, BF931143, BE827975, AA557715, BG122019, AV747893, AA862807, T09167, AW771700, AI338369, AI808072, AA453634, AA100486, BF987667, BF931921, AA774221, BG059802, BE539623, AA101981, AA884482, R16694, BF887393, AW749084, BF338616, AA768482, AW473754, AW198229, AA357596, AA379498, AK027528.1, AF290613.1, BC005021.1, BC003387.1, BC003612.1, AF020797.2, AK023863.1, AF225424.1, AF090900.1, AK026865.1, AL133640.1, AK025084.1, AB060916.1, AB063046.1, AL122093.1, AL136749.1, BC008488.1, AL512719.1, AL512754.1, AK026532.1, AK024538.1, AL359601.1, AB055361.1, AK000137.1, AF106862.1, X82434.1, AK025092.1, AL050149.1, AL122121.1, S78214.1, AB063070.1, AL137527.1, AF104032.1, AL512733.1, AL512746.1, AF091084.1, AB060912.1, AL359615.1, AB019565.1, AF090901.1, AL122050.1, AL133560.1, AF090934.1, AB060826.1, AK027096.1, AL359618.1, BC008387.1, BC002733.1, AL162006.1, BC001045.1, AB060852.1, AL442082.1, AK026542.1, AL133606.1, AL049314.1, AK000083.1, AB052200.1, AL136892.1, BC006195.1, BC007021.1, AL117460.1, AK026452.1, AL359941.1, AL162083.1, AK000445.1, AK026045.1, AB060863.1, AB048954.1, AF125948.1, AK026592.1, AB051158.1, AB048953.1, AB047904.1, AL133080.1, BC008899.1, AF218014.1, AB063008.1, AK026959.1, Z82022.1, AB060908.1, AL133075.1, BC003687.1, AF097996.1, BC006807.1, AL137459.1, AJ242859.1, AL117435.1, AL049452.1, BC008417.1, AL137550.1, AF090943.1, AL050277.1, AL110196.1, AK026741.1, AB060825.1, AL136789.1, AF090903.1, AL136799.1, AL157431.1, AB055315.1, AF078844.1, BC007199.1, AL136928.1, BC001967.1, AK025339.1, AK026608.1, AL359596.1, AL110221.1, AL117457.1, AK026534.1, AL050116.1, AL353940.1, AF090896.1, AL049464.1, AL389978.1, AK026784.1, BC008365.1, AL080124.1, AK000618.1, AL050108.1, AK026533.1, AK026744.1, AB056420.1, AL133016.1, AL137557.1, AF219137.1, AL136586.1, AL049466.1, AK000652.1, AK027868.1, AK026504.1, Y16645.1, AL136844.1, AB062938.1, AB055303.1, AB055368.1, AB060887.1, AL050146.1, AL050393.1, AL122123.1, AK027113.1, U42766.1, AB047615.1, AB055366.1, AK025491.1, AL117585.1, AF125949.1, AB049758.1, AF111847.1, AL442072.1, AL117394.1, AK026855.1, AK026647.1, AF177336.1, BC003683.1, AK025772.1, AF146568.1, AL389982.1, AL137283.1, AK026583.1, AL117583.1, AL136768.1, AL512718.1, AL133565.1, AL080060.1, AL133557.1, AL096744.1; BC004556.1, AL133093.1, AL136787.1, AK025414.1, AF207829.1, AK000212.1, BC008070.1, AL390167.1, AK024524.1, AL049300.1, AL049938.1, AB048964.1, AK000432.1, AK025958.1, AK027204.1, AL110225.1, AL080137.1, AL136845.1, AB056768.1, U91329.1, AK025967.1, AL049382.1, AF183393.1, BC004951.1, AK026353.1, AL050138.1, AK026086.1, BC002839.1, AL136786.1, AB056421.1, AK027213.1, AB047801.1, AK026927.1, AL359583.1, BC008485.1, AL512689.1, X65873.1, AK025391.1, AL122098.1, AK000323.1, AL133113.1, AK000614.1, AB052191.1, AL512750.1, AL049430.1, AL137271.1, AL080127.1, AK025524.1, AF260566.1, U80742.1, BC008382.1, AK027164.1, AK026629.1, AK024588.1, AL050024.1, BC008280.1, AK026947.1, AB060929.1, AK000718.1, AL137463.1, AL122110.1, X72889.1, AL137648.1, AK025632.1, AL512765.1, AK000647.1, AL512684.1, AL137521.1, BC008983.1, AL512761.1, AL137538.1, AK026630.1, AB056809.1, AL162062.1, AK025484.1, AK027116.1, BC005168.1, AK026526.1, AL359622.1. HTNBK13 223 831967 1-1146 15-1160 BE799670, BE794458, BF969839, BF116235, BE894258, AI755110, BE693669, AA209372, AA209368, AV702645, AW957276, AV724122, AW517214, AW173346, AA197278, AI609300, BF726226, AI261762, BE882052, AI400083, AA112077, AI242204, AA114827, AA314213, AI741473, AI828740, AI982748, AA197243, AI140451, BF923463, AA838629, AA854805, AA114846, N59363, AA931373, AA972617, BF358017, AI687104, AA234016, AA843577, AA625125, AA133768, AA911212, AI553981, AA304885, AA133767, R76792, AI559186, AW874604, BF358016, BE180724, AA486696, BG248840, AA733214, R75956, H24319, AA447346, AW839247, AA633116, AI187039, AA877750, AA938362, AA083910, AA384854, N32060, H23039, AA678500, F16874, AA972329, T84723, AW372424, AW372436, AA906710, AW372421, AW372425, AW372444, AW372435, AW372434, AW372427, AW372439, BF897466, AW372423, AW062891, AW372443, AW372420, AW372440, AW372433, AW372437, AW372422, AW372432, AW372442, AW372430, AW372428, AW372419, AW372429, AI383049, AI383050, AW372431, AI702272, AI701769, AW372274, AW372408, AA092723, AA634344, AW805484, AI623944, AI985597, AW073164, AW372407, AA352209, AW749114, AW629894, AA912615, AA825365, AA029876, H55702, BE814640, AA975153, T52666, AI540674, AW073898, AA857847, AA808175, AV721824, AI298026, AW834282, AW952443, AI287233, AI784233, BE966278, AA809897, AL514721, AI698391, AI500714, BE905211, AI978703, BE874163, AA868961, AW051088, AL514025, AI570884, AI250627, AW827249, AI366900, AV713528, AI633125, AI538564, AI915291, AW152182, BE393784, BE843239, AI582932, AI590043, BF970040, BF811804, AI889189, AL514511, BF724894, AA641818, AI866469, BE965208, AI884318, AI638644, AI570056, W74529, AI804983, AL513779, BF814449, AI699823, AI345745, AL514871, AV733582, AI351959, BE896769, AI628337, AL513999, BG026483, AI610714, AW189332, AV726590, BF811802, AI538885, AI274507, AI423198, AV753074, AL043070, AI521005, AI621341, BG029667, AI571966, AI539690, AI500061, AI702527, AI741158, AW020693, BG105241, AI927233, AI979129, AL514279, BF970768, AI670002, BE881211, BE964961, BE963575, BE967219, AA928539, AV712722, BF089679, AI559524, BE964506, AI583558, AI499570, AW020095, BE784335, AL514455, AI811603, BF750875, AI473536, AL513911, AI922215, AL041150, N33175, AL515033, R41605, AW072349, BF812426, R32821, AV726058, AL513631, AL514357, AL513907, AI815232, BG031068, AL121365, AI859991, BF885082, BE880084, AI872423, AL050345.1, AL021707.2, AL136686.1, AB015347.1, BC008839.1, BC008899.1, AK026959.1, Y10936.1, AK026647.1, AB060893.1, AK027137.1, AL512765.1, AL133637.1, AL389935.1, AL136808.1, AB050431.1, AL110269.1, AL049283.1, AF143723.1, BC002733.1, AF141289.1, AL122100.1, BC001056.1, AL133010.1, AB060877.1, BC002343.1, BC006494.1, AK000250.1, AF184965.1, S78453.1, AB060863.1, BC004925.1, AB047947.1, M85164.1, AK026462.1, BC009311.1, AL049938.1, BC001967.1, AL122045.1, AL080156.1, AL080148.1, AL137480.1, S76508.1, AK024538.1, AF097996.1, BC004899.1, AK026045.1, AK026613.1, AL137284.1, AF155827.1, AL117648.1, BC008063.1, BC005858.1, BC004195.1, BC002372.1, AF058921.1, AF199509.1, AL110218.1, AK000502.1, BC007920.1, BC005825.1, AK024992.1, AL137530.1, AL080110.1, S77771.1, AK024747.1, BC001199.1, BC002697.1, AC020910.5, BC004945.1, X00474.1, AK026744.1, AL110228.1, AL117394.1, AB047904.1, Z82022.1, BC008285.1, AL136747.1, AK025708.1, AL110225.1, BC004556.1, AL133623.1, AK025889.1, AL137627.1, AJ406939.1, AL049382.1, BC002409.1, AL050280.1, AF090903.1, AL137533.1, BC006287.1, AF227198.1, D83032.1, AF177340.1, BC008920.1, AL136850.1, AK024594.1, BC004530.1, AF069506.1, AF232009.1, BC007926.1, BC004513.1, Y14314.1, AL157482.1, AL133049.1, AL110280.1, AL133665.1, BC006414.1, AB049849.1, BC004991.1, AL110196.1, AL133080.1, AB050410.1, AB047623.1, AK027173.1, AL137574.1, AL137711.1, AB055368.1, AK025312.1, AF274348.1, BC002473.1, AF274347.1, AL133112.1, AK026408.1, BC003658.1, X82434.1, BC009221.1, AF245044.1, BC000253.1, AL080159.1, BC002809.1, BC003614.1, BC004222.1, AK025375.1, AL137523.1, BC005168.1, AK026741.1, BC008037.1, AB056809.1, BC003684.1, AL359941.1, AK026550.1, AK024588.1, AL049339.1, AB055361.1, BC008836.1, AL137560.1, AF217987.1, AL080139.1, AL137529.1, AL389982.1, AK000653.1, BC007499.1, AL137276.1, AF076464.1, AB060912.1, AB048953.1, AB060876.1, AK000103.1, AL390184.1, AB062938.1, AK025435.1, BC005165.1, AK000257.1, AL136893.1, AB052200.1, AF262032.1, AL136754.1, AL137488.1, AL080126.1, BC004191.1, AL050092.1, AF230402.1, AF098162.1, AL137550.1, AK000690.1, BC005002.1, AK026534.1, AL162083.1, BC008781.1, AK026547.1, BC005805.1, AK026480.1, BC008686.1, AK025339.1, BC003101.1, BC007347.1, AL133075.1, BC002466.1, AK026927.1, AK025857.1, AL136842.1, AL137716.1, AF285167.1, AL162006.1, AL136615.1, BC008918.1, BC006164.1, BC006410.1, AK000630.1, AF183393.1, BC007556.1, AK025254.1, AK027142.1, BC004416.1, AY026527.1, AL133113.1, AL162004.1, AB055315.1, AL356859.12, AL080162.1, AL137526.1, AK000603.1, BC004370.1, BC009310.1, BC006103.1, BC003056.1, BC001652.1, AL117416.1, AL137459.1, BC003569.1, AK000083.1, BC000090.1, AF132730.1, D83989.1, AK027152.1, AK000323.1, AL353956.1, BC001844.1, BC004264.1, BC001969.1. HTOAM11 224 664508 1-1186 15-1200 AV756491, AW500684, AI821931, AI755214, BF725844, AI754567, AI754105, AW576251, AW340905, AL079734, AL040374, BF879045, AA126763, AI732430, AI380617, T74524, AL120343, BE138594, AA535216, AA533054, AI732458, AA127499, AI821714, AI792133, AI791913, AA602906, BF725761, AI923052, BF868994, AA714110, BE704103, AI821785, AI358712, AW504168, BF526964, AI755202, H07953, AW961593, AI066646, AW302711, AI144081, AA515733, AA704393, AW407632, AV764259, AW732205, AW973992, BE139267, AW157456, AW957600, AW162697, AV737160, BF917346, AV760941, AI669421, AI357823, AA862227, AA659832, AW275971, AI300054, AW079761, AW502873, BF724838, AA715814, BF977305, AI312309, AA700943, AP001486.4, AC083868.2, AC006970.6, AC027124.4, AL050335.32, AC009144.5, AC006368.2, AC007011.1, AC005821.1, AC008569.6, AP002360.4, AC022211.5, AL117334.29, AF038458.1, AC016027.15, AC003101.1, AL159977.10, AF107045.1, AC011464.5, AP001719.1, AC012627.4, AC016830.5, AL137792.11, AF207550.1, AL121594.6, AC007850.29, AL031845.6, AC073964.3, AC022148.5, AC015853.8, AC008962.8, AC008372.6, AC008551.5, AC003046.3, AL355392.7, AP000493.1, AL355094.3, AC024163.2, AC020916.7, AC011461.4, AC004840.3, AP001710.1, AC006120.1, AC004841.2, AL157838.24, AC005932.1, AC002395.1, AC005874.3, AF134471.1, AC00101.15, AC004526.1, AL117381.32, Z83822.1, AC004125.1, AC025593.5, AC005756.1, AL450339.5, AC007227.3, Z83826.12, AC011479.6, AP002812.3, AC005512.1, AC027130.5, AL035460.15, AC004386.1, AL513008.14, AJ297357.1, AJ251973.1, AC010463.6, AC084373.24, AF312032.1, AC016770.10, AL136126.34, AL109804.41, AL121890.34, AC011005.7, AC005231.2, AL445201.14, AC087071.2, AC005702.1, AC006141.2, AP001670.1, AL078463.11, AL109915.10, Z97632.1, AC005291.1, AC016025.12, AC006468.9, AL133453.3, AL109797.18, AL121601.13, AC005212.1, AC004821.3, AC006285.11, AF254822.1, AP001759.1, M37468.1, AC009244.24, AC002300.1, AC008969.5, AL160264.22, AC004089.25, AC020947.6, AC016026.13, AL356299.16, AC009996.7, AC016596.5, AC000115.1, AC005015.2, AC008857.5, AC005274.1, AL354932.26, AL022721.1, AC009068.10, AC009812.17, AL135927.14, AC005071.2, AC005081.3, AL136980.5, AF053356.1, AL139396.17, AC002314.1, AL139021.6, AC005225.2, AL096841.6, AL022313.1, AL138756.23, AC090532.1, AC007114.7, AC008753.8, AC006236.1, AP001717.1, AC011442.5, AC068533.7, AC005793.1, AC008755.6, AC004598.1, AL135752.6, AC018836.4, AC005971.5, AC005914.1, AL049872.3, AL353692.14, AL355497.14, AC002350.1, AL035587.5, U96629.1, AC011497.6, AP000455.4, AC008124.8, AC005839.1, AF168787.1, AL136137.15, AC007318.4, AL359397.3, AC005091.1, AC078846.2, AC007845.12, AL109976.23, AL138717.6, AL139809.16, AC005695.1, AC009530.5, AL133382.8, AC006345.4, AC004166.12, AC010358.5, AL354836.13, AC006211.1, AL133312.3, AC069255.18, AL353804.22, AC004858.2, AC002429.1, AC008770.6, AL139022.4, AL162390.9, AL008730.1, AC011465.4, AC090941.1, AP001672.1, AL023284.1, AL096701.14, AF067844.1, AC005041.2, AC022415.5, AC006077.1, Z85996.1, AL353602.10, AP000555.1, AL352984.4, AC021036.5, AL031658.11, AL034420.16, AC010854.3, AC005215.1, AL133548.6, AL031602.14, AC016769.10, AC011470.5, AC016776.6, AL031276.1, AP002436.3, AC005606.2, AC012379.7, AC005280.3, AL591076.5, AP000045.1, AP000113.1, Z99716.4, AC006026.2, AL590763.1, AL160492.5, AL035410.7, AC034207.4, AC002476.1, AC008812.7, AC013726.7, AC018764.6, AL035455.30, AL390252.9, AL118501.22, AL109743.4, AL136228.8, AC018811.4, AC008267.6, AL133545.10, AL390917.12, AC007057.3, AC026172.3, AC009086.5, AC010319.7, AC004973.1, AC008155.9, AF225899.1, AC007193.1, AL133215.16. HTODH83 225 580884 1-1967 15-1981 HTODN35 226 570901 1-1580 15-1594 AC009079.4. HTPCO75 227 853645 1-1453 15-1467 BF969488, BG109664, BG113966, BF980916, BF970168, BE465437, AA913515, BF667561, N47676, AI984260, AI561226, BE502740, AI016617, BG150307, AW665914, BE081361, BE710057, AA279712, BE220910, AI880662, AI812005, AI223871, AW449123, AA460500, BF184599, N47675, BF243896, AU145432, AA829587, AA931455, T05743, AI685691, BG121044, AA256899, R56024, AA654665, R56025, N51207, BF853453, AI808712, AI765168, BF589254, AW936494, AA910986, BE836669, BF114747, AW377241, AL050136.1, AK021741.1, AC002067.1, Z92542.2. HTTCB60 228 853401 1-1490 15-1504 AL527596, AL530567, AI114859, BE407719, AL527597, AL529809, AI830718, AI640304, BF447073, AI862404, AI419019, BE899304, AA496239, AI889002, AL514080, BF000126, AI200382, BE048538, AA442132, AI798632, AI140806, AI565622, AU156790, AA834046, AW294987, AI183801, W68566, AI872891, AA456203, AI364465, AI765479, BE645691, AI468507, BF477789, AI672711, W68567, AI187099, AW135628, AI417504, AI004499, AA815198, AL526637, AI371368, Z19140, AI349321, AI074599, AA442131, AL529295, AA610289, AI620803, W73758, AW880750, BE782057, AI002625, AU136598, BG122646, AA496240, AI298503, AW339508, BE467855, AI310364, AI346793, W73592, AI926388, AW452176, AI884667, AI183908, AW470742, AA593079, N92388, AW771410, AU144823, AW172442, AI086796, AW104502, AW572529, AI381931, AA707604, AI640676, AW571951, AI868834, AI313208, AI861943, AA719132, AW471200, AI990933, AI193543, AI193748, AI921195, AA903834, AW023979, AI825347, AI861932, AI919371, AI248156, AI694324, AA442774, AA701903, BF433373, BF063027, AA885026, AA723857, BF001754, BF588721, AI916136, AI686495, BF062018, AI990711, BF060737, AI202906, AW471024, AI675788, AI910996, AW663382, AW770995, BG057507, BF110069, BE670537, BF114632, AA427828, AI537838, AI130863, AI651012, AI148378, AA780173, AW079270, AA621634, AI571348, W95356, AA010215, AF206673.2, AK001914.1, AP000501.1, AF298153.1, AK027296.1, AL110244.1, AB040964.1, AL137610.1. HTTDN24 229 766485 1-1978 15-1992 AL513751, BG035744, BE792734, BE535814, AI968100, AI638191, AI962526, AW590203, AW593447, AW590212, BE541446, BE220296, AA205663, BE564856, BF769037, AI968771, AI632511, AW250856, AA205775, AA205709, BF843264, AA773929, N53214, AA486579, N30623, AI655137, AW014522, BE564422, AI742717, BF028977, BE672098, AA777617, AI146844, AW577576, AI159827, AA563660, BF027920, AI637620, AI078792, AI990191, BF062933, BF062045, AW044164, BF770158, AA256059, N32225, BF769030, BF769032, BF445417, AA486679, AW959397, W22630, AA554325, R59984, AW006249, AW236554, AW577601, AA765281, AI653704, AI206329, R67166, AW243537, AA205674, H00645, T16860, AA256068, N57321, H00733, N41868, T16861, AI149479, AI906144, N59086, BF926652, AA909318, AW594490, AA299517, N58615, AA641283, AA644247, AW236428, AI820831, BG009693, BF851615, AA743510, Z42234, AA834460, AA548119, AI672532, F07004, Z40114, F01762, AA301407, BF085945, BF931293, AA205611, AI638784, BF085928, AA983380, BF059602, AW192770, BE714630, AA205702, AI078796, BC001039.1, AF310106.1, BC003592.1, AK000784.1, AK025952.1, AF298547.1, AK026387.1. HTTEE41 230 840950 1-1959 15-1973 AL533251, AL514520, AL535565, AL519250, AU120401, AL514519, AL513606, AL517678, AI986262, AU139509, AU138912, BF797374, AU124362, AV714807, AI970836, T25350, BG169633, AU126517, BG031251, AA854925, AI683290, AI084631, AU130264, BE748699, AU124315, AU133858, BG109529, AU135232, AI080278, BG119840, AI114754, BG258768, BG255494, BE786284, AI955296, AU126258, BG254492, BF057590, AI342485, BE907879, AV689488, BG035949, AV688329, BE780740, AI982815, BE897302, AL037847, BE619295, BF037149, BE547405, BE540421, BE870861, BG119545, BE891546, BE872237, BG179989, BE784107, AI992184, AU128577, BE893297, BE798745, AI858401, BE871280, BE882225, AI801143, BE748021, BG033360, BF984307, BF795054, BE535364, BE870845, AV711098, BG115930, BE787681, BE542328, BE872802, BF700048, BF695387, AI674907, BE439607, BF984686, AW079041, BG166631, BE896320, BE541060, BG168465, BF212903, BG165234, BF036631, AW276472, AI469127, BG116642, AW304879, BG035549, BE298292, BE383409, AW951669, BE789205, AA876301, AI559157, BE618039, BE569054, BE884211, AA314410, AL037869, BF034922, BG261406, BE278215, AI567289, AI216294, BE536033, AA160646, BE541100, AI652229, BF793118, AA573870, BE781061, AW675729, AV717435, AW967121, AW268555, AW614767, BE871948, BF246592, AW302409, BG231674, AL519249, AI623915, AA633523, BG056451, AI554391, BF593678, AL513605, AA541705, BE536986, BE540075, BE893524, BF211942, AW403677, BE302004, BF030769, AA639701, AW675653, BG114666, BF305722, AI812111, AI003845, AI922596, AI610416, BE874043, AI690769, AI423245, BE884372, AI041880, BE972270, BE277936, AI970618, BE564025, AA569371, BE536189, AW517408, BF692138, AA838062, AW675629, BE544390, AA665762, AI129259, AI018744, AV717173, BE563964, BE278405, AU155033, AA779219, AA935682, AA306144, AA307298, AA707035, BF241179, BF207700, BE018391, BE964282, AA916194, BE567396, AA928532, AW197045, AA740956, AA877985, AI081121, AV751536, AA102457, AA160479, AA192686, AA574025, AU146473, AV739405, AA242865, AI249678, AA081834, AI566278, BF212412, AA188046, BF242025, AL517677, W22339, AV748102, AW001935, AU157811, AA634515, AI151103, AI027752, AV752496, AA031432, BE535794, AA838373, BG166698, AW023950, AA514375, BE540980, BE222647, AI027493, AA308098, AI499910, AU150842, AI537313, BE258575, AW468963, AA665209, BF208112, AI288710, AI074560, AA758489, AA307507, AU128978, AL121077, AA224142, BE551072, AU152253, AI589777, AA242864, AA865406, AI086547, AA159666, AI082436, AW953920, AA143173, BE909718, AW089251, AI240700, W72593, AI919263, AF026166.1, AF026293.1, U91327.1, T55193, T70199, T88741, T91070, R11411, R12294, R12806, R19161, R25132, R25131, H02506, H02507, H54342, H56330, H63377, H63378, N21157, N29115, N70633, N98764, W00501, W02093, W05515, W30995, W32188, W45121, W52697, W76587, AA022658, AA022740, AA031431, AA047132, AA045726, AA053378, AA053093, AA084605, AA136549, AA142896, AA151835, AA151836, AA159771, AA187179, AA192116, AA224141, AA233936, AA232345, AA488991, AA534693, AA586488, AA623003, AA740505, AA829738, AA829916, AA876221, AA932434, AA933813, AA968745, AA969795, AI089838, D81695, N84531, C00761, N87565, C14312, C14469, AA641463, C17845, AA209312, AA401491, AA400238, AA598835, AA644299, AA705865, AA723334, AA852740, AA852739, AI076109, T23525, T16205, T27335, T27402. HTWEH94 231 561680 1-1347 15-1361 AA459162, BE143033, AC004858.2, AF109907.1, AL050349.27, AC008755.6, AC010320.9, AL356915.19, AF053356.1, AF312032.1, AC020916.7, AC011895.4, AC020906.6, AF134726.1, AC004253.1, AC008738.6, AC020908.6, AL133387.8, AC002126.1, AC005522.2, AC005620.1, AC078818.19, AL359091.10, AC005052.2, AC004089.25, AC005071.2, AL160269.14, AC006312.8, U91321.1, AC005015.2, AL137792.11, AC004826.3, AC007374.6. HTXDG92 232 658730 1-1148 15-1162 BF034514, AW027319, AA393485, R62243, AI810717, BE999941, W69160, W69286, W57903, AA631235, AI766161, AI860626, AW453087, BF991821, AA485564, AA148470, AI298594, BF107486, BE048342, AW440613, AI684022, BF110344, R69650, AW958450, R69664, H51376, AA036897, AI869096, AA501595, BF910477, AI936365, AA503611, AI962698, H00843, AI473149, BF513848, AA036898, R21268, AA355015, BE393026, AW028218, BE265190, R21267, AA400786, BF917732, BF917734, BF872260, AA485403, W57902, AA209160, AI620837, R22871, BE622738, BF907430, AA148471, AI824248, BE907695. HTXET11 233 581521 1-975 15-989 AC012076.4. HTXFA72 234 853410 1-1847 15-1861 AW007854, BE677425, AW297663, AC008102.17, AC067742.5, AC012476.8, AC007637.9, AC004887.2, AC007383.4, AP000426.3, AC020916.7, AC006538.1, AC025166.7, AL133325.20, AL121754.18, AC024075.4, AL109758.2, AP001574.3, AL080243.21, AC002365.1, AL499604.9, AC005702.1, AL121905.23, AC008738.6, AL049832.3, AC011491.5, AC020744.4, AC004953.1, Z84484.1, AC006559.6, AC008440.8, AC003101.1, AL157827.17, AL133214.12, AC008946.6, AL357498.16, AC003046.3, AL161793.9, AC011895.4, AC011442.5, AC009756.9, AL157838.24, AC004973.1, AL133448.4, AC008699.5, AL356019.5, AC002119.1, AC008537.5, AC011461.4, AC074295.7, AC037475.9, AC015842.9, AC008379.6, AC004707.1, U91321.1, AC010458.5, AC001231.2, AC002310.1, AL050318.13, AL118559.6, AC006409.2, AC005529.7, AC011472.7, AC005670.1, AC005342.1, AL451083.5, AC005995.3, AC023490.5, AC009951.9. HTXJD85 235 840391 1-1103 15-1117 BF511613, R16403, H06356, AC005874.3, AF134471.1, AC018828.3, AC022383.3, AC005261.1, AL031588.1, AL132653.22, AC008649.6, AP000689.1, AB003151.1, AC005080.2, Z94056.1, AF243527.1, AC011308.8, AC016637.6, AL355074.5, AL391259.15, AC018808.4, AL355543.13, AC034193.4, AC008569.6, AC001231.2, AL354720.14. HTXJY08 236 637774 1-1173 15-1187 BG163801, BE892293, AW467952, AI273661, AA937102, AI400753, AA937101, AI571239, Z45153, N44737, AA359719, AL049162, BF754319, BE888980, AC004757.1, AC005962.1. HTXLT36 237 843477 1-1026 15-1040 BF038509, BE907863, AW450318, BF064162, AA846547, BF090743, AI743758, AW452088, AI038546, AV721433, AI124936, BF221659, AW961339, W88912, AI038218, AI468531, AI401419, AA312153, D12023, AA361016, AI024136, AI308237, AI763043, AA722378, AW043671, AA304380, AA329556, AI917526, BF507852, AW901911, AA483331, AW969635, AA280698, AI524566, BE898992, C75284, AC006160.9. HUFCL31 238 801938 1-1446 15-1460 AI821606, AI791844, AW050605, AA573825, AI660560, AI826629, AI304327, AW009962, AI262416, AI983793, AI984141, AI660493, AI991272, AI274929, AI281211, AA593860, AA618335, AI346155, AI732165, AI821178, AA469031, AI695625, AI924216, BF917041, AI921289, Z57552.1, Z59954.1. HUKDF20 239 566823 1-1091 15-1105 AL133246.2, AL392023.3, AC008572.6. HUSCJ14 240 894699 1-3328 15-3342 AL530386, AL530385, BE740541, BE793159, BE746303, BG111869, BE743225, BE740593, BE876261, AW025458, BE796028, BE872615, BE877735, BE744205, BF314587, BE378561, AW953416, BF965802, BG254323, AW964183, BE746753, BF981839, BG248382, BF340579, BE740789, BF697703, AV759552, BE395111, AI991200, BG178345, BE547992, BG180982, BG170659, AI245997, BE296958, BF218155, BE874752, BG250326, BE537584, BE892651, W37330, AA454974, BE621103, BG249254, AW880574, BE315071, AA724393, AW401755, BF981216, BF724854, BE740318, AW602164, AA176450, AI798066, BF529155, BF590827, BE938687, AA528038, AA176930, BE007448, BG260090, AA744235, BE019877, AI755131, BE019722, AA258968, BE007599, AA888876, BE206323, AA454975, W49835, AI658890, AI400439, BE855719, BE965617, AI369432, AI378678, AI814475, BE894966, BE255155, N33371, H30709, AI817038, AI079528, AA988238, AI094675, BE296010, BG055258, BE698523, BF749938, AA781122, BG008471, BE007089, AI078131, BG012658, H28137, AA636058, BF112108, H30791, W52270, AI582733, AI150949, AA410493, AA860936, AA132898, AI278541, BF112247, BE044217, BF507690, AA933024, H66966, AA258022, BE247272, AA310300, BE208182, AA256356, H30612, H24913, N47554, AA595919, AA921999, BF772395, AW883922, AI050086, BF820414, AA326738, H66965, W52173, AW630747, AA987810, BF841176, BF841178, H24636, BF886659, AW025934, R85382, AA176415, AW997264, BE769213, BE873578, AA213621, AA213747, AI090506, AI350930, AI335914, R88068, BE315307, AA306524, R78161, BF772700, BF755261, R25528, BE698518, AA367585, BF880127, BG163239, AW964548, R88419, BE833357, R67073, AW168072, AI866652, R66194, W39693, BF512635, AI921135, R77799, BE742426, R88069, Z25017, BE005706, T52535, AI084635, AW272406, BE005705, AA368103, AA485159, H44289, H21572, AA335920, AA132726, BE007543, W37836, AI080447, T72649, R23331, AI800373, H11232, AI493270, AA633490, R61159, R48336, R45587, AW591739, BE315089, AA375973, AA091597, AI961784, AW140066, R61873, BF806323, BF342050, Z28722, AI003986, AW608071, T30986, H10607, R48240, AA143657, T72717, AA378816, AW768907, H28184, AA320516, W45049, BF743131, N47553, BF115823, AA988048, AI698305, AI342699, AA410492, AA176682, AA366872, BF432748, AW895119, AA329961, AA873382, N51170, AI802557, AW947291, BF432749, AI468036, BE315041, BE814237, H10399, AL045269, AI307370, T52614, AI310496, AW879611, AA463709, AW842163, BE245828, AI364211, AA485063, D20903, BE181425, BE281137, AW998715, AL080223.1, AC007040.2. HUVDJ48 241 564853 1-1813 15-1827 AI479925, AV720735, AI886110, AF261918.1, AB037733.1. HWBBU75 242 780360 1-2717 15-2731 BG254332, BG258993, AW189216, AW189167, BG110226, AA621650, AI524238, AW027302, AI085248, AI187104, AJ403112, AW129561, AA287508, AA287381, AI569606, AW137239, AI814239, BE246677, BF356218, H87267, AI831754, H87322, W15561, AA831701, AA808000, BE086121, AW137386, AA932127, H92853, BF916818, R84247, BE672348, BF869463, AI380578, BE696648, N80792, AA811717, AA922507, BF945407, AK024474.1. HWBCN36 243 722259 1-994 15-1008 AL031296.1. HWBDJ08 244 762860 1-2071 15-2085 BG029349, AW384103, AI653230, AW384082, AI719268, BG150070, AW404710, AW590965, AI952047, AW474522, BF514114, AA074214, AA770535, AI952951, AI138532, AA156247, AW474480, AV727834, AI655852, AI656352, AI424794, AI199860, BE867482, AI377297, AA885793, AW236695, AA909918, AI650687, AA632416, AA147540, BF896398, BF896399, AA205078, AA730888, AA709293, AW016441, AA906134, AI350684, BE243783, BE243699, AA074296, F29482, AW770135, AA971473, AI825691, AW818041, BE184408, BE244905, BG236422, AL048135, AW575000, U51144, AV738383, BC002538.1, AL133351.33, AL356785.18, AL049245.1, AC083875.1, AC006050.1, AC004408.1, AL136443.11, AL008719.1, AL391259.15, AL445237.16, AC007030.3, AC002416.1, AL390798.3, AC011242.8, AC004491.1, AP000696.1, AL034422.24, AC004966.2, AC003950.1, AL163285.2, AL133342.14, AP001726.1, Z94056.1, AL162231.20, AL121781.38, AC018502.5, AC090426.1, AC022392.4, AF003627.2, AF279660.2, U91323.1, AL160281.17, AC006948.4, AC020942.5, AC026416.4, AC073316.6, AC011816.17, Z84469.1, AL354889.14, AC079383.17, AC090957.1, AL360088.5, AB026898.1, AL135783.6, AL391122.9, AC012377.5, AL138849.12, U52111.2, AC004552.1, AC010789.9, AC004953.1, AL079303.3, AL118559.6, AL049758.11, AC003046.3, AC023426.29, AC068724.7, AC004033.3, AL138752.5, AC005037.2, AL162385.16, AC020913.6, AF029308.1, AP002982.2, AL121656.2, AL356575.8, AC006443.1, AP001753.1, AC079141.7, AP003534.1, AC008440.8, AC009623.6, AC005912.1, AC006313.1, AP003467.2, AC073655.26, AF111168.2, AC008806.4, AL137787.11, AC004865.1, AC002476.1, AL138756.23, AC051619.7, AC091493.1, AC087071.2, AL121754.18, AC005886.2, AC003071.1, AL139193.4, Z84487.2, AC011742.3, AL031005.1, AP000011.2, AL049838.3, U82828.1, AL161935.10, AP001728.1, AL031577.1. HWLBO67 245 834315 1-522 15-536 AC011739.7. HWLGP26 246 834770 1-1884 15-1898 AL529987, AV699741, BF530871, AW207742, AI638032, BE540656, AI469103, AW575118, BE503442, AI652512, AA928729, AW592532, AI419960, AI057140, BF102699, AI365238, AI392687, N49757, AA832314, BF819685, AI025113, AI767982, AA766124, AU151363, AW402473, AI654109, AW070683, AI738949, AA815032, BG231904, AW578625, AI365240, AV688777, AA769270, AW613566, AA605050, AI459543, AI885560, AW361738, AV689923, AA046663, BE242932, BF895261, AA507121, AA046576, AI627311, AW296010, AA814924, BG253328, BE789823, BE243489, AA298793, AI458707, AI208523, AA694217, BE247085, AW137352, AV689313, AA077726, BE241524, AL523598, AV685517, BE241950, AV697781, AV691130, AV688018, AV697631, N52685, AW182301, AA910584, AA126044, AW390687, AL529988, AF176097.1, AK023002.1, AJ131891.2. HILCA24 247 869856 1-1968 15-1982 BE780749, AU137314, AV732875, AW954734, AW138881, BF681107, AI079555, AI624252, AA233208, AU157126, AI734898, AW088851, BE221267, AA314962, AV715966, AA971982, AA233124, AA129416, AA133798, AA886808, AA353195, AW132033, T98200, H50558, AI888751, AI818363, BF917932, BF926224, AI784628, H50559, T98201, AK001989.1, AL512750.1, AC010627.5, AC010491.3, AC026749.5, AC016656.5, AC016652.5. HYABC84 248 865064 1-1464 15-1478 BE619984, BG180257, BG253753, BE546940, BE795721, BE871790, BE538846, AW953562, AA524254, AW978620, AW970777, AW001609, AI798108, AU159275, AU148477, AA524480, AA476556, AW027610, BE207925, AW166935, AL521960, AI934516, AU149354, AW291597, AW974311, AA443023, AI186348, AI597811, AI692241, N32579, BE619316, AI689448, AW152379, AI271524, AI093466, AI870536, AI149215, AI432467, AA854903, AA781886, AI199164, AI744310, AL043754, AI372057, BF725035, AI269272, AW770362, AA399350, AI367106, AA463464, AA812239, AW516985, W48832, AW151757, AI086901, AW571473, AW514611, AA292378, AI079461, BE206384, AA934644, AI269712, AW189899, AA588341, AA676478, AA126131, AW055258, AW166860, N70058, AA916656, AI874191, AW297040, AW083905, AW664480, AA427894, AA453450, AA843278, AI687474, AA620899, W49813, AA860641, AI692799, BE676833, AA306455, AA292016, T63718, AW236228, AW304861, AW772846, AW468035, BE964404, AI015326, AW662269, AA226903, AW090569, AA304032, AA915898, R56660, AW194056, AA293296, AA047874, H28877, AW076091, AI126745, AA482627, R50813, AA482480, AI674616, BF926901, AA045575, R68388, W37626, H01650, AA598596, AW364253, N59135, AL045883, N23722, AA908894, Z40636, R38774, R68593, AV708320, AI474604, R47766, AI611825, AA022933, BE829256, BF244825, AA888168, F03832, C04718, AA534374, BE297735, R50403, R56826, R81871, T33719, AI569605, N41917, AW731635, AW050454, BF737093, Z44868, AI648412, T06476, AA428005, W37625, BF893080, BF820895, BF769768, F07587, F01530, D54185, AI611777, AA902145, AA338785, Z25279, BE617105, F00464, AA084935, BE241564, R10512, AI627173, BE252263, AA022983, AV743083, BE940174, N75173, BE929227, H28878, AA094149, AW294418, AI261764, AA449769, T63873, AI885556, AA775981, BE710635, BE936751, BC008836.1, BC001323.1, AL117480.1, AL132825.35, AF055022.1, AL096738.1. HPWTF23 249 844775 1-1994 15-2008 AL519322, AL519321, AL528621, AL525472, AV708533, AV707483, BG117131, AV701688, AW954252, AV701690, AL525317, BF968790, AV709370, AV707363, AV657517, AI635895, AL036882, AW857209, AL036883, AV707606, BF128575, BG121441, BE295239, AW392020, BF311431, AV762694, AV706829, AA523541, BE073173, BE295817, BF514386, BE675214, AI949219, AW262884, BE858056, BG055038, BG249916, BG037033, AW371034, AI674706, AI708919, AV715587, AA535070, AA679292, AW022838, N50052, BE830095, AU148045, BE870349, BE349624, BE350028, BF837239, AA147899, BF845844, AW073776, AU147814, BF725674, AI368808, AI927857, AI342463, AV701888, AI140105, AA487093, AV750709, BE858057, AW190710, AA147844, AI096573, AA716187, AA722314, AI862165, W63717, AW262935, AA906753, AL525667, AV748474, AI269618, AI760874, AI074133, AA662310, AI924825, AI309724, AW468063, AA613662, W76557, AI089512, AI984192, AI707646, AA459957, AI624320, BE164613, BF967589, AW029309, AI640395, AI128327, AW176265, AW167854, AA040063, W46859, AI570042, AA618091, AI144525, AA010681, AI379204, AA460046, AA862301, AA599534, AV743247, BE138816, AV650781, W67232, AA971998, AI310729, N62277, AI597921, AI978845, AI671691, AI766634, W72563, AW316882, AI570060, AA135362, R52727, AW468339, AA516433, AW276147, AI800083, AI572626, AI272092, AI368167, N50029, AI865786, AI708598, AW316956, BE063387, AW007919, BF725145, AV650618, AV661271, T63404, AW243982, AA394163, AA431390, AV739478, AA018926, N47564, AV736149, AI480119, AW263269, AI039111, AV650298, W60279, AA765950, AA775091, AV741361, AI672788, W92333, AI913079, AA602156, AA010680, AI312732, W58299, AI718214, AV744886, AI865478, W46821, AW338299, AA115222, AA026509, AA833692, T65926, BE676820, AW629236, AV760664, AV744890, AW512231, AI272268, T79429, AI420676, AI933008, AI720397, H44638, AI699112, W58190, AA318908, BE160746, AA576196, T60058, AA318968, AA335541, AA507838, AL038891, BE244391, AI567253, T33201, AI422399, BE242438, F28371, W92390, T27118, AV660511, AI198237, AA279281, T32253, AA987730, AI521033, AI582582, AA137239, W65468, H26544, AA115157, AI377668, BE245885, AA953911, BE241874, AI587551, R22214, AI918377, AW779069, AA953835, AV760987, T79517, AW263932, W65469, AI524412, BE241477, AI955974, AW023746, BE160914, AV746796, AI216726, BE831539, AI184048, AI598049, AA148643, AI246336, AI538030, W46870, T60102, BE179366, AI224380, F09314, AW663101, T63029, AA043646, AA302796, T65354, BE243054, BE063421, T30199, AY007119.1, AF183393.1, AF228339.1, AB025432.1, AF153603.1, AL110191.1, Z50781.1, T63278, T64499, R22268, R34893, R49280, R49280, H43597, R86094, N47563, N54684, N54707, N77565, W60371, W67342, AA019007, AA148642, AA190663, AA464495, AA464496, AA427718, AA429282, AA244422, AA244455, AA551457, D79925, N85667, C20552, AA652629, AA652778, AA292345, AA293158, AA293176, AA292756, AA432382, AA835434, AA909440, T24090, D45452, F11656, F11926, F09572. HLWAU42 250 695737 1-933 15-947 BF575615, BF248388, AI743425, N36954, AW025235, BF589732, AI806452, AW020533, AA917950, AI127390, AI828595, BF695312, AI275973, BF671395, AA173611, AI246128, AI373941, BE857030, AA132201, N33440, BE878264, AI217284, AI969577, AI242521, W67395, N93171, AA525797, AW504320, AW874661, AA670252, AA131236, BE813584, AW844409, AW014620, AA573687, AW440586, W67250, BF575996, N51666, AA953867, N42414, H98104, AW069360, AA131940, H96912, AA613814, BF155640, AA953290, AI049610, AI525660, AA173610, AW375401, AI370204, AI370185, F09577, H05159, H27178, T65023, AA730005, AW799253, H25040, AW337747, BE544553, AA601931, AW994202, AW882494, AW021670, BF081928, BE000561, AI149153, AW956671, BF095801, BE392121, W38797, AA131357, BF095790, BF224114, BE813540, AL049471.1. HGCAC19 251 851527 1-5047 15-5061 AL527635, AI582588, BE619956, AW003219, AW195551, AI114573, BE888827, BF444977, AU139098, AA307878, AI915534, AU117064, BE466128, BG251218, BE619434, AI700569, AI823371, BG260998, AI625554, AI478557, AW958690, AI052694, AW963950, AL134475, AU136749, BE326684, AW770747, AI803406, AI990669, BF448130, AW770442, AI193790, AI659257, AV757384, AI669806, BE835313, AI917737, AA947974, BE881668, BE466358, AI698025, BF061334, BF433914, BE551956, AW003148, BF055107, AW237192, BE646481, AW949672, AA910441, AA994008, AA804520, AW058531, AI247672, BE890358, AA156928, AI767577, AW949361, AW166817, BG104926, AI971146, AW299771, AI990108, AI631706, BG114047, AA824598, AA156804, AA312557, AA677603, AI636032, AI400786, BE768656, AI199770, AI989485, AA155855, AI802754, AV650187, AW014065, BF677900, BF680207, AA557259, AI925305, AA446690, AI261268, AW150014, AA155958, BE379872, BF215025, AW867051, BE672462, BE168338, AI350222, AI624072, AI825185, AA436183, AA916694, AA436309, AW867047, BE139075, BF530119, AI656311, AV755927, AV746485, AW770099, AA147323, BE768554, AI885519, BE768542, AA446565, AI821288, BE245294, AW129764, AA599626, AW818369, BE245262, AI536551, AI040161, AI446564, AI627777, AA020816, AV758283, D80771, AA806383, AA136672, H40373, BE042467, AA013438, AI591292, AW472897, AI821040, AI820997, AA180321, AI356314, AA312855, AI610014, BF902177, AW195825, C75219, AW015240, AI936012, AI219472, AA086094, AW169820, AW983970, AA113317, AI282736, BE175626, BF061715, AI275943, AW294050, AV738635, AA358726, AA463692, BF896130, AW183617, H21867, BE168125, AI246262, AA059237, AA677761, AA628617, BE768595, AI625290, AA007519, BE768665, AW374169, AA355425, T07209, AA377468, AW271631, AA152212, AW189878, AA086093, AW594290, AA742173, AI949786, AW023249, AW750461, AA256785, BE872264, AA709003, AA147425, AA361135, H40320, AW392416, AW392849, BF081349, AI038854, AW188893, BE763982, AA976161, AA345273, AW858464, AW891017, D52302, AA358727, AI699855, D61215, D52967, AA430996, AW376216, R81478, AW501079, AA007520, AA353267, AA728991, AA304423, AA356393, AI370683, AW024132, T71726, AA361495, AV724116, AI888048, BF844493, T40389, BF089968, T71578, AA621423, AW043940, AA513522, BF763717, R62569, BF950322, AA334984, BF091136, BE892057, AW188923, AA826001, N24122, BE768735, AW382160, BF985865, T18537, BF365430, AI830982, AW452149, AW188842, BE702825, AI637868, AA732593, AA376840, AW858513, BF804806, D19713, AW131746, AA256511, AA829191, AI310882, AF109907.1, L40392.1, AK026107.1, AC004858.2, S67071.1, AF135593.1, AC006345.4, T60745, R25599, R26428, R26995, AA136788, AA150143, AA888518, AI053404, AI053507, AI053899, N64912, N64913, C00711, AA393814, AA905385, AI002840. HEQBJ01 252 876546 1-2777 15-2791 AU123703, AI744148, AI744113, AU130720, BE897357, BG105308, AU137281, BF308835, AI860811, AI889014, AI765413, BE546221, BE670583, AW237314, BG248530, AW952369, BE502734, BE503479, AI765401, BE540301, AL042645, BF212478, AW500417, BG249708, AW674190, AI867571, BE018153, AW293518, AA534578, AI432178, AW169762, AA506984, BE389321, AA420605, AI142237, AA406169, AW591668, AW188054, AI147954, AA430324, AL040186, AI197943, AW502601, AI589634, AA569041, AI015938, AA433904, AA070872, AI188829, AI124780, AA421239, AI149224, AA420647, AI916160, W73655, AI076564, AI768356, BF592904, BE464156, AW772442, BE219974, AI638215, BG034042, AI125307, R51293, BE812953, W51790, AA172002, AA425349, AA565222, AA313542, AA825728, R35270, AW204507, BF306159, BG152825, AA100809, W28763, BF223048, AI222042, AI479185, W26572, W45413, W73608, R52192, AI160529, AW440819, AI422286, AI298011, AA171761, AA421279, R51403, H62930, R52097, R59309, BF880022, AA581790, W81419, BF844067, AI768849, W40121, AI708313, AW511347, AA373236, AW368276, BF844000, AA434583, AV747735, Z42217, BE702753, W81420, AI962360, AA325784, BF879714, R59310, AI271621, T25845, BF879715, T06069, F05246, BF880008, AA806028, Z38264, AA071023, AA815452, N54389, BE929180, BE929187, BE929175, BF092052, AA810542, AA383377, AI370602, R50941, T87272, BF149192, T87186, AW867815, F01748, AA947741, BF749400, AA773493, AA890049, AW591526, AI985779, AA984284, BF923416, AW272799, AL043147, AB007891.1, BC002701.1, AC009079.4, AL157384.8, AK025058.1, AK026926.1, AC009779.18. HBJHT01 253 587262 1-1237 15-1251 AW572853, AW852662, AW794904, AW852694, AA494184, BE092308, AW467441, BG000611, BF871414, BF871418, AA715850, AW962959, AI281561, BF899671, AI537814, BF899672, BF970033, BF899670, AW975902, BF847493, AW197990, AC084865.2, AL590763.1, AC008403.6, AC002551.1, AP001858.4, AP001692.1, AL450224.1, AL160269.14, AL022476.2, AL049762.20, AC011811.42, AL356020.3, AC078818.19, AC007842.1, AC007055.3, AC008569.6, AC005803.1, AB020865.1, AL353574.8, AL138836.15, AJ277546.2, Z93930.10, AC005484.2, AC069548.4, AC007619.22, L44140.1, AL158040.13, Z95115.1, AF196779.1, AC009155.3, AP003116.2, AC005548.1, AL354696.11, AC005254.1, AL353579.17, AC012323.7, AC007371.16, AL049780.4, AC000353.27, AL022336.1, AC009309.4, AL158830.17, AC005488.2, AL591076.5, AC007954.7, AL031664.1, AC000025.2, AL121586.31, AC004859.2, AL365364.19, AL049757.14, AL390205.17, AC007011.1, AL353812.13, AL157877.11, AP000893.5, AL021391.2, AC087244.17, Y10196.1, AF001549.1, U91323.1, AL096701.14, AC034193.4, AP000501.1, AC022211.5, AC011472.7, AP002852.3, AL031650.22, AC008745.6, AC011005.7, AC006930.1, AF053356.1, AL133174.15, AL137918.4, AP001715.1, AC018808.4, AC009488.5, AC027319.5, AL110115.38. HE8FD92 254 901142 1-3963 15-3977 BG252727, BG260973, BG180624, BG122157, BE887548, AW948984, AW950907, BF965913, AI905469, BE869433, BG032175, AV718334, AV650921, BF793347, BE148077, BF793887, BG120463, BF204516, AW969050, BG121940, AL045343, AV649638, BE621758, AL037725, BE620934, BG169462, AV708063, AL045344, BE892224, AV708871, AV649666, AV653240, AV721974, BF740216, BG110357, AI888249, AV649944, AI814624, BE615208, BE613500, BE540375, AL043485, AA401244, BG117844, AV705742, AV762287, AW614902, AI768623, AA404260, W95853, BE614234, AW167131, BE542745, BF844095, AW955266, BE551076, AI800419, AL040955, AL040932, BF891913, N32025, BF028570, BF980034, BE147946, AA315005, AL531145, AW020997, AI523819, BE162196, AV689195, AW196856, AL048907, BF378885, BE615086, AW851278, AW948982, AW069571, BF219231, AW664296, BF839881, BE299495, AI859769, AI804043, BE615260, AW439581, AI979070, AW873118, BG028790, AW173627, AW138481, BF836425, BE090183, AW470149, W95142, AI954566, AW966417, AW382691, AA431381, AI923608, AI920788, BF836432, BG028439, AI074015, AW401596, AI096566, AA777093, AW168867, BE350092, AI872178, AL040146, BF832429, BG179393, AW196804, AI634706, AI400065, AI983052, AL044108, BF571648, AW874528, AI200933, W94444, AI080172, AI073801, AV728394, BG107927, AA614709, AW963612, AA134828, BE349345, AA463288, AA625480, AA953123, BE537489, AI589346, AW261884, BF757706, AI026817, AI654244, BE140097, AA932332, AV649957, AW002764, AI435532, N51228, AA725887, AI685954, AI247070, R97631, AI142752, AI569997, W81307, AI473795, AA962014, AA946853, AI916323, AW382688, AW954051, BF725969, AI000904, N69326, AA774786, AI445189, AI348365, BF433144, C17016, BE764894, AW193468, AI274717, AI420632, AI471592, AL040335, N94040, AA134827, BE156276, W94957, BE181110, AW452484, AV726157, AI077452, AI675925, AW675613, AV694497, AV683792, AA868559, AA504467, AV684722, AI241864, AI826322, AA448916, AA872701, AA398843, BE966521, BF940653, BF804717, BG036364, AI865471, AW474946, AI088270, BE046420, BE764877, W45368, H27416, AV649926, AW020365, AV649742, AW241206, AV649875, BE857361, AA431829, BF923515, AI359458, AI439074, W94259, AL045559, BF998123, T78688, AI174662, AW377563, AV649995, BE764899, AI094039, AW797490, AA463197, AA494404, AI520933, AA609501, AV659915, AV662147, AI125505, BG111536, AI167605, AI149616, AV698723, AA609104, AI913467, BE835924, BF197860, AV651144, AA431425, AA975219, AA635251, BE710504, BE816681, D61350, AI811787, AV734255, AA341676, AV662120, AI368857, AA630621, AF131738.1, AB051480.1, AL117237.1, AL136890.1, AL022240.8, AL359752.11, AL049715.25, AB033071.1, AL050141.1, AK000726.1, Y14436.1, T49441, T49442, T65179, T90631, T79315, T79742, T83158, T85864, R16090, R15724, R18665, R22674, R38982, R39314, R41620, R43379, R41620, R43379, H24497, H29599, H44475, H65354, H65563, N69549, W17223, W40134, W92875, W95598, W95599, AA045010, AA194855, AA470492, AA470959, AA483167, AA514556, AA557980, AA729817, AA738229, AA805073, AA908302, AA911490, AA938675, AA962188, AA976144, N55792, N74638, N83414, C01293, N88703, C14561, C14674, C15258, C15727, C15842, AA091964, AA094573, AA095891, AA247583, AA449426, AA599645, AA663625, AA665721, AA813724, AI003102, T10450, D31148, F11837, AA694588, AI251461, AI270073, AI280943, AI582507, AI126993, AI203813, AI247468. HBDAB91 255 864374 1-993 15-1007 AI167963, AA782398, BE043035, AW081006, W07319, R23362, N75825, AW195519, BE858969, AI701657, R45349, AI468816, AW858522, AW577199, AL135012, BE927373, AW601637, BF084778, AL134110, AL134524, AW577201, AL045327, AL045494, AL042523, AW577192, AL045328, BF910726, AL042420. Description of Table 4

Table 4 provides a key to the tissue/cell source identifier code disclosed in Table 1B.2, column 5. Column 1 of Table 4 provides the tissue/cell source identifier code disclosed in Table 1B.2, Column 5. Columns 2-5 provide a description of the tissue or cell source. Note that “Description” and “Tissue” sources (i.e. columns 2 and 3) having the prefix “a_” indicates organs, tissues, or cells derived from “adult” sources. Codes corresponding to diseased tissues are indicated in column 6 with the word “disease.” The use of the word “disease” in column 6 is non-limiting. The tissue or cell source may be specific (e.g. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ). Furthermore, tissues and/or cells lacking the “disease” designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder. In numerous cases where the tissue/cell source is a library, column 7 identifies the vector used to generate the library. TABLE 4 Code Description Tissue Organ Cell Line Disease Vector AR022 a_Heart a_Heart AR023 a_Liver a_Liver AR024 a_mammary gland a_mammary gland AR025 a_Prostate a_Prostate AR026 a_small intestine a_small intestine AR027 a_Stomach a_Stomach AR028 Blood B cells Blood B cells AR029 Blood B cells activated Blood B cells activated AR030 Blood B cells resting Blood B cells resting AR031 Blood T cells activated Blood T cells activated AR032 Blood T cells resting Blood T cells resting AR033 brain brain AR034 breast breast AR035 breast cancer breast cancer AR036 Cell Line CAOV3 Cell Line CAOV3 AR037 cell line PA-1 cell line PA-1 AR038 cell line transformed cell line transformed AR039 colon colon AR040 colon (9808co65R) colon (9808co65R) AR041 colon (9809co15) colon (9809co15) AR042 colon cancer colon cancer AR043 colon cancer (9808co64R) colon cancer (9808co64R) AR044 colon cancer 9809co14 colon cancer 9809co14 AR050 Donor II B Cells 24 hrs Donor II B Cells 24 hrs AR051 Donor II B Cells 72 hrs Donor II B Cells 72 hrs AR052 Donor II B-Cells 24 hrs. Donor II B-Cells 24 hrs. AR053 Donor II B-Cells 72 hrs Donor II B-Cells 72 hrs AR054 Donor II Resting B Cells Donor II Resting B Cells AR055 Heart Heart AR056 Human Lung (clonetech) Human Lung (clonetech) AR057 Human Mammary Human Mammary (clontech) (clontech) AR058 Human Thymus Human Thymus (clonetech) (clonetech) AR059 Jurkat (unstimulated) Jurkat (unstimulated) AR060 Kidney Kidney AR061 Liver Liver AR062 Liver (Clontech) Liver (Clontech) AR063 Lymphocytes chronic Lymphocytes chronic lymphocytic leukaemia lymphocytic leukaemia AR064 Lymphocytes diffuse large Lymphocytes diffuse large B cell lymphoma B cell lymphoma AR065 Lymphocytes follicular Lymphocytes follicular lymphoma lymphoma AR066 normal breast normal breast AR067 Normal Ovarian Normal Ovarian (4004901) (4004901) AR068 Normal Ovary 9508G045 Normal Ovary 9508G045 AR069 Normal Ovary 9701G208 Normal Ovary 9701G208 AR070 Normal Ovary 9806G005 Normal Ovary 9806G005 AR071 Ovarian Cancer Ovarian Cancer AR072 Ovarian Cancer Ovarian Cancer (9702G001) (9702G001) AR073 Ovarian Cancer Ovarian Cancer (9707G029) (9707G029) AR074 Ovarian Cancer Ovarian Cancer (9804G011) (9804G011) AR075 Ovarian Cancer Ovarian Cancer (9806G019) (9806G019) AR076 Ovarian Cancer Ovarian Cancer (9807G017) (9807G017) AR077 Ovarian Cancer Ovarian Cancer (9809G001) (9809G001) AR078 ovarian cancer 15799 ovarian cancer 15799 AR079 Ovarian Cancer Ovarian Cancer 17717AID 17717AID AR080 Ovarian Cancer Ovarian Cancer 4004664B1 4004664B1 AR081 Ovarian Cancer Ovarian Cancer 4005315A1 4005315A1 AR082 ovarian cancer 94127303 ovarian cancer 94127303 AR083 Ovarian Cancer 96069304 Ovarian Cancer 96069304 AR084 Ovarian Cancer 9707G029 Ovarian Cancer 9707G029 AR085 Ovarian Cancer 9807G045 Ovarian Cancer 9807G045 AR086 ovarian cancer 9809G001 ovarian cancer 9809G001 AR087 Ovarian Cancer Ovarian Cancer 9905C032RC 9905C032RC AR088 Ovarian cancer 9907 C00 Ovarian cancer 9907 C00 3rd 3rd AR089 Prostate Prostate AR090 Prostate (clonetech) Prostate (clonetech) AR091 prostate cancer prostate cancer AR092 prostate cancer #15176 prostate cancer #15176 AR093 prostate cancer #15509 prostate cancer #15509 AR094 prostate cancer #15673 prostate cancer #15673 AR095 Small Intestine (Clontech) Small Intestine (Clontech) AR096 Spleen Spleen AR097 Thymus T cells activated Thymus T cells activated AR098 Thymus T cells resting Thymus T cells resting AR099 Tonsil Tonsil AR100 Tonsil geminal center Tonsil geminal center centroblast centroblast AR101 Tonsil germinal center B Tonsil germinal center B cell cell AR102 Tonsil lymph node Tonsil lymph node AR103 Tonsil memory B cell Tonsil memory B cell AR104 Whole Brain Whole Brain AR105 Xenograft ES-2 Xenograft ES-2 AR106 Xenograft SW626 Xenograft SW626 AR119 001: IL-2 001: IL-2 AR120 001: IL-2.1 001: IL-2.1 AR121 001: IL-2_b 001: IL-2_b AR124 002: Monocytes untreated 002: Monocytes untreated (1 hr) (1 hr) AR125 002: Monocytes untreated 002: Monocytes untreated (5 hrs) (5 hrs) AR126 002: Control.1C 002: Control.1C AR127 002: IL2.1C 002: IL2.1C AR130 003: Placebo-treated Rat 003: Placebo-treated Rat Lacrimal Gland Lacrimal Gland AR131 003: Placebo-treated Rat 003: Placebo-treated Rat Submandibular Gland Submandibular Gland AR135 004: Monocytes untreated 004: Monocytes untreated (5 hrs) (5 hrs) AR136 004: Monocytes untreated 004: Monocytes untreated 1 hr 1 hr AR139 005: Placebo (48 hrs) 005: Placebo (48 hrs) AR140 006: pC4 (24 hrs) 006: pC4 (24 hrs) AR141 006: pC4 (48 hrs) 006: pC4 (48 hrs) AR152 007: PHA (1 hr) 007: PHA (1 hr) AR153 007: PHA (6 HRS) 007: PHA (6 HRS) AR154 007: PMA (6 hrs) 007: PMA (6 hrs) AR155 008: 1449_#2 008: 1449_#2 AR161 01: A - max 24 01: A - max 24 AR162 01: A - max 26 01: A - max 26 AR163 01: A - max 30 01: A - max 30 AR164 01: B - max 24 01: B - max 24 AR165 01: B - max 26 01: B - max 26 AR166 01: B - max 30 01: B - max 30 AR167 1449 sample 1449 sample AR168 3T3P10 1.0 uM insulin 3T3P10 1.0 uM insulin AR169 3T3P10 10 nM Insulin 3T3P10 10 nM Insulin AR170 3T3P10 10 uM insulin 3T3P10 10 uM insulin AR171 3T3P10 No Insulin 3T3P10 No Insulin AR172 3T3P4 3T3P4 AR173 Adipose (41892) Adipose (41892) AR174 Adipose Diabetic (41611) Adipose Diabetic (41611) AR175 Adipose Diabetic (41661) Adipose Diabetic (41661) AR176 Adipose Diabetic (41689) Adipose Diabetic (41689) AR177 Adipose Diabetic (41706) Adipose Diabetic (41706) AR178 Adipose Diabetic (42352) Adipose Diabetic (42352) AR179 Adipose Diabetic (42366) Adipose Diabetic (42366) AR180 Adipose Diabetic (42452) Adipose Diabetic (42452) AR181 Adipose Diabetic (42491) Adipose Diabetic (42491) AR182 Adipose Normal (41843) Adipose Normal (41843) AR183 Adipose Normal (41893) Adipose Normal (41893) AR184 Adipose Normal (42452) Adipose Normal (42452) AR185 Adrenal Gland Adrenal Gland AR186 Adrenal Gland + Whole Adrenal Gland + Whole Brain Brain AR187 B7(1 hr) + (inverted) B7(1 hr) + (inverted) AR188 Breast (18275A2B) Breast (18275A2B) AR189 Breast (4004199) Breast (4004199) AR190 Breast (4004399) Breast (4004399) AR191 Breast (4004943B7) Breast (4004943B7) AR192 Breast (4005570B1) Breast (4005570B1) AR193 Breast Cancer Breast Cancer (4004127A30) (4004127A30) AR194 Breast Cancer Breast Cancer (400443A21) (400443A21) AR195 Breast Cancer Breast Cancer (4004643A2) (4004643A2) AR196 Breast Cancer Breast Cancer (4004710A7) (4004710A7) AR197 Breast Cancer Breast Cancer (4004943A21) (4004943A21) AR198 Breast Cancer (400553A2) Breast Cancer (400553A2) AR199 Breast Cancer Breast Cancer (9805C046R) (9805C046R) AR200 Breast Cancer Breast Cancer (9806C012R) (9806C012R) AR201 Breast Cancer (ODQ Breast Cancer (ODQ 45913) 45913) AR202 Breast Cancer Breast Cancer (ODQ45913) (ODQ45913) AR203 Breast Cancer Breast Cancer (ODQ4591B) (ODQ4591B) AR204 Colon Cancer (15663) Colon Cancer (15663) AR205 Colon Cancer Colon Cancer (4005144A4) (4005144A4) AR206 Colon Cancer Colon Cancer (4005413A4) (4005413A4) AR207 Colon Cancer Colon Cancer (4005570B1) (4005570B1) AR208 Control RNA #1 Control RNA #1 AR209 Control RNA #2 Control RNA #2 AR210 Cultured Preadipocyte Cultured Preadipocyte (blue) (blue) AR211 Cultured Preadipocyte Cultured Preadipocyte (Red) (Red) AR212 Donor II B-Cells 24 hrs Donor II B-Cells 24 hrs AR213 Donor II Resting B-Cells Donor II Resting B-Cells AR214 H114EP12 10 nM Insulin H114EP12 10 nM Insulin AR215 H114EP12 (10 nM insulin) H114EP12 (10 nM insulin) AR216 H114EP12 (2.6 ug/ul) H114EP12 (2.6 ug/ul) AR217 H114EP12 (3.6 ug/ul) H114EP12 (3.6 ug/ul) AR218 HUVEC #1 HUVEC #1 AR219 HUVEC #2 HUVEC #2 AR221 L6 undiff. L6 undiff. AR222 L6 Undifferentiated L6 Undifferentiated AR223 L6P8 + 10 nM Insulin L6P8 + 10 nM Insulin AR224 L6P8 + HS L6P8 + HS AR225 L6P8 10 nM Insulin L6P8 10 nM Insulin AR226 Liver (00-06-A007B) Liver (00-06-A007B) AR227 Liver (96-02-A075) Liver (96-02-A075) AR228 Liver (96-03-A144) Liver (96-03-A144) AR229 Liver (96-04-A138) Liver (96-04-A138) AR230 Liver (97-10-A074B) Liver (97-10-A074B) AR231 Liver (98-09-A242A) Liver (98-09-A242A) AR232 Liver Diabetic (1042) Liver Diabetic (1042) AR233 Liver Diabetic (41616) Liver Diabetic (41616) AR234 Liver Diabetic (41955) Liver Diabetic (41955) AR235 Liver Diabetic (42352R) Liver Diabetic (42352R) AR236 Liver Diabetic (42366) Liver Diabetic (42366) AR237 Liver Diabetic (42483) Liver Diabetic (42483) AR238 Liver Diabetic (42491) Liver Diabetic (42491) AR239 Liver Diabetic (99-09- Liver Diabetic (99-09- A281A) A281A) AR240 Lung Lung AR241 Lung (27270) Lung (27270) AR242 Lung (2727Q) Lung (2727Q) AR243 Lung Cancer Lung Cancer (4005116A1) (4005116A1) AR244 Lung Cancer Lung Cancer (4005121A5) (4005121A5) AR245 Lung Cancer Lung Cancer (4005121A5)) (4005121A5)) AR246 Lung Cancer Lung Cancer (4005340A4) (4005340A4) AR247 Mammary Gland Mammary Gland AR248 Monocyte (CT) Monocyte (CT) AR249 Monocyte (OCT) Monocyte (OCT) AR250 Monocytes (CT) Monocytes (CT) AR251 Monocytes (INFG 18 hr) Monocytes (INFG 18 hr) AR252 Monocytes (INFG 18 hr) Monocytes (INFG 18 hr) AR253 Monocytes (INFG 8-11) Monocytes (INFG 8-11) AR254 Monocytes (O CT) Monocytes (O CT) AR255 Muscle (91-01-A105) Muscle (91-01-A105) AR256 Muscle (92-04-A059) Muscle (92-04-A059) AR257 Muscle (97-11-A056d) Muscle (97-11-A056d) AR258 Muscle (99-06-A210A) Muscle (99-06-A210A) AR259 Muscle (99-07-A203B) Muscle (99-07-A203B) AR260 Muscle (99-7-A203B) Muscle (99-7-A203B) AR261 Muscle Diabetic (42352R) Muscle Diabetic (42352R) AR262 Muscle Diabetic (42366) Muscle Diabetic (42366) AR263 NK-19 Control NK-19 Control AR264 NK-19 IL Treated 72 hrs NK-19 IL Treated 72 hrs AR265 NK-19 UK Treated 72 hrs. NK-19 UK Treated 72 hrs. AR266 Omentum Normal (94-08- Omentum Normal (94-08- B009) B009) AR267 Omentum Normal (97-01- Omentum Normal (97-01- A039A) A039A) AR268 Omentum Normal (97-04- Omentum Normal (97-04- A114C) A114C) AR269 Omentum Normal (97-06- Omentum Normal (97-06- A117C) A117C) AR270 Omentum Normal (97-09- Omentum Normal (97-09- B004C) B004C) AR271 Ovarian Cancer Ovarian Cancer (17717AID) (17717AID) AR272 Ovarian Cancer Ovarian Cancer (9905C023RC) (9905C023RC) AR273 Ovarian Cancer Ovarian Cancer (9905C032RC) (9905C032RC) AR274 Ovary (9508G045) Ovary (9508G045) AR275 Ovary (9701G208) Ovary (9701G208) AR276 Ovary 9806G005 Ovary 9806G005 AR277 Pancreas Pancreas AR278 Placebo Placebo AR279 rIL2 Control rIL2 Control AR280 RSS288L RSS288L AR281 RSS288LC RSS288LC AR282 Salivary Gland Salivary Gland AR283 Skeletal Muscle Skeletal Muscle AR284 Skeletal Muscle (91-01- Skeletal Muscle (91-01- A105) A105) AR285 Skeletal Muscle (42180) Skeletal Muscle (42180) AR286 Skeletal Muscle (42386) Skeletal Muscle (42386) AR287 Skeletal Muscle (42461) Skeletal Muscle (42461) AR288 Skeletal Muscle (91-01- Skeletal Muscle (91-01- A105) A105) AR289 Skeletal Muscle (92-04- Skeletal Muscle (92-04- A059) A059) AR290 Skeletal Muscle (96-08- Skeletal Muscle (96-08- A171) A171) AR291 Skeletal Muscle (97-07- Skeletal Muscle (97-07- A190A) A190A) AR292 Skeletal Muscle Diabetic Skeletal Muscle Diabetic (42352) (42352) AR293 Skeletal Muscle Diabetic Skeletal Muscle Diabetic (42366) (42366) AR294 Skeletal Muscle Diabetic Skeletal Muscle Diabetic (42395) (42395) AR295 Skeletal Muscle Diabetic Skeletal Muscle Diabetic (42483) (42483) AR296 Skeletal Muscle Diabetic Skeletal Muscle Diabetic (42491) (42491) AR297 Skeletal Muscle Diabetic Skeletal Muscle Diabetic 42352 42352 AR298 Skeletal Musle (42461) Skeletal Musle (42461) AR299 Small Intestine Small Intestine AR300 Stomach Stomach AR301 T-Cell + HDPBQ71.fc T-Cell + HDPBQ71.fc 1449 16 hrs 1449 16 hrs AR302 T-Cell + HDPBQ71.fc T-Cell + HDPBQ71.fc 1449 6 hrs 1449 6 hrs AR303 T-Cell + IL2 16 hrs T-Cell + IL2 16 hrs AR304 T-Cell + IL2 6 hrs T-Cell + IL2 6 hrs AR306 T-Cell Untreated 16 hrs T-Cell Untreated 16 hrs AR307 T-Cell Untreated 6 hrs T-Cell Untreated 6 hrs AR308 T-Cells 24 hours T-Cells 24 hours AR309 T-Cells 24 hrs T-Cells 24 hrs AR310 T-Cells 24 hrs. T-Cells 24 hrs. AR311 T-Cells 24 hrs T-Cells 24 hrs AR312 T-Cells 4 days T-Cells 4 days AR313 Thymus Thymus AR314 TRE TRE AR315 TREC TREC AR316 Virtual Mixture Virtual Mixture AR317 B lymphocyte, B lymphocyte, AR318 (non-T; non-B) (non-T; non-B) AR326 001 - 293 RNA (Vector 001 - 293 RNA (Vector Control) Control) AR327 001: Control 001: Control AR328 001: Control.1 001: Control.1 AR355 Acute Lymphocyte Acute Lymphocyte Leukemia Leukemia AR356 AML Patient #11 AML Patient #11 AR357 AML Patient #2 AML Patient #2 AR358 AML Patient #2 SGAH AML Patient #2 SGAH AR359 AML Patient#2 AML Patient#2 AR360 Aorta Aorta AR361 B Cell B Cell AR362 B lymphoblast B lymphoblast AR363 B lymphocyte B lymphocyte AR364 B lymphocytes B lymphocytes AR365 B-cell B-cell AR366 B-Cells B-Cells AR367 B-Lymphoblast B-Lymphoblast AR368 B-Lymphocytes B-Lymphocytes AR369 Bladder Bladder AR370 Bone Marrow Bone Marrow AR371 Bronchial Epithelial Cell Bronchial Epithelial Cell AR372 Bronchial Epithelial Cells Bronchial Epithelial Cells AR373 Caco-2A Caco-2A AR374 Caco-2B Caco-2B AR375 Caco-2C Caco-2C AR376 Cardiac #1 Cardiac #1 AR377 Cardiac #2 Cardiac #2 AR378 Chest Muscle Chest Muscle AR381 Dendritic Cell Dendritic Cell AR382 Dendritic cells Dendritic cells AR383 E. coli E. coli AR384 Epithelial Cells Epithelial Cells AR385 Esophagus Esophagus AR386 FPPS FPPS AR387 FPPSC FPPSC AR388 HepG2 Cell Line HepG2 Cell Line AR389 HepG2 Cell line Buffer 1 hr. HepG2 Cell line Buffer 1 hr. AR390 HepG2 Cell line Buffer 06 hr. HepG2 Cell line Buffer 06 hr AR391 HepG2 Cell line Buffer 24 hr. HepG2 Cell line Buffer 24 hr. AR392 HepG2 Cell line Insulin HepG2 Cell line Insulin 01 hr. 01 hr. AR393 HepG2 Cell line Insulin HepG2 Cell line Insulin 06 hr. 06 hr. AR394 HepG2 Cell line Insulin HepG2 Cell line Insulin 24 hr. 24 hr. AR398 HMC-1 HMC-1 AR399 HMCS HMCS AR400 HMSC HMSC AR401 HUVEC #3 HUVEC #3 AR402 HUVEC #4 HUVEC #4 AR404 KIDNEY NORMAL KIDNEY NORMAL AR405 KIDNEY TUMOR KIDNEY TUMOR AR406 KIDNEY TUMOR AR407 Lymph Node Lymph Node AR408 Macrophage Macrophage AR409 Megakarioblast Megakarioblast AR410 Monocyte Monocyte AR411 Monocytes Monocytes AR412 Myocardium Myocardium AR413 Myocardium #3 Myocardium #3 AR414 Myocardium #4 Myocardium #4 AR415 Myocardium #5 Myocardium #5 AR416 NK NK AR417 NK cell NK cell AR418 NK cells NK cells AR419 NKYa NKYa AR420 NXYa019 NKYa019 AR421 Ovary Ovary AR422 Patient #11 Patient #11 AR423 Peripheral blood Peripheral blood AR424 Primary Adipocytes Primary Adipocytes AR425 Promyeloblast Promyeloblast AR427 RSSWT RSSWT AR428 RSSWTC RSSWTC AR429 SW 480(G1) SW 480(G1) AR430 SW 480(G2) SW 480(G2) AR431 SW 480(G3) SW 480(G3) AR432 SW 480(G4) SW 480(G4) AR433 SW 480(G5) SW 480(G5) AR434 T Lymphoblast T Lymphoblast AR435 T Lymphocyte T Lymphocyte AR436 T-Cell T-Cell AR438 T-Cell, T-Cell, AR439 T-Cells T-Cells AR440 T-lymphoblast T-lymphoblast AR441 Th 1 Th 1 AR442 Th 2 Th 2 AR443 Th1 Th1 AR444 Th2 Th2 H0002 Human Adult Heart Human Adult Heart Heart Uni-ZAP XR H0003 Human Adult Liver Human Adult Liver Liver Uni-ZAP XR H0004 Human Adult Spleen Human Adult Spleen Spleen Uni-ZAP XR H0008 Whole 6 Week Old Uni-ZAP XR Embryo H0009 Human Fetal Brain Uni-ZAP XR H0011 Human Fetal Kidney Human Fetal Kidney Kidney Uni-ZAP XR H0012 Human Fetal Kidney Human Fetal Kidney Kidney Uni-ZAP XR H0013 Human 8 Week Whole Human 8 Week Old Embryo Uni-ZAP XR Embryo Embryo H0014 Human Gall Bladder Human Gall Bladder Gall Bladder Uni-ZAP XR H0015 Human Gall Bladder, Human Gall Bladder Gall Bladder Uni-ZAP XR fraction II H0018 Human Greater Omentum, Human Greater Omentum peritoneum Uni-ZAP XR fII remake H0019 Human Fetal Heart Human Fetal Heart Heart pBluescript H0022 Jurkat Cells Jurkat T-Cell Line Lambda ZAP II H0024 Human Fetal Lung III Human Fetal Lung Lung Uni-ZAP XR H0026 Namalwa Cells Namalwa B-Cell Line, Lambda ZAP II EBV immortalized H0028 Human Old Ovary Human Old Ovary Ovary pBluescript H0030 Human Placenta Uni-ZAP XR H0031 Human Placenta Human Placenta Placenta Uni-ZAP XR H0032 Human Prostate Human Prostate Prostate Uni-ZAP XR H0033 Human Pituitary Human Pituitary Uni-ZAP XR H0036 Human Adult Small Human Adult Small Small Int. Uni-ZAP XR Intestine Intestine H0038 Human Testes Human Testes Testis Uni-ZAP XR H0039 Human Pancreas Tumor Human Pancreas Tumor Pancreas disease Uni-ZAP XR H0040 Human Testes Tumor Human Testes Tumor Testis disease Uni-ZAP XR H0041 Human Fetal Bone Human Fetal Bone Bone Uni-ZAP XR H0042 Human Adult Pulmonary Human Adult Pulmonary Lung Uni-ZAP XR H0046 Human Endometrial Human Endometrial Uterus disease Uni-ZAP XR Tumor Tumor H0047 Human Fetal Liver Human Fetal Liver Liver Uni-ZAP XR H0049 Human Fetal Kidney Human Fetal Kidney Kidney Uni-ZAP XR H0050 Human Fetal Heart Human Fetal Heart Heart Uni-ZAP XR H0051 Human Hippocampus Human Hippocampus Brain Uni-ZAP XR H0052 Human Cerebellum Human Cerebellum Brain Uni-ZAP XR H0053 Human Adult Kidney Human Adult Kidney Kidney Uni-ZAP XR H0056 Human Umbilical Vein, Human Umbilical Vein Umbilical vein Uni-ZAP XR Endo. remake Endothelial Cells H0057 Human Fetal Spleen Uni-ZAP XR H0059 Human Uterine Cancer Human Uterine Cancer Uterus disease Lambda ZAP II H0060 Human Macrophage Human Macrophage Blood Cell Line pBluescript H0061 Human Macrophage Human Macrophage Blood Cell Line pBluescript H0063 Human Thymus Human Thymus Thymus Uni-ZAP XR H0068 Human Skin Tumor Human skin Tumor Skin disease Uni-ZAP XR H0069 Human Activated T-Cells Activated T-Cells Blood Cell Line Uni-ZAP XR H0070 Human Pancreas Human Pancreas Pancreas Uni-ZAP XR H0071 Human Infant Adrenal Human Infant Adrenal Adrenal gland Uni-ZAP XR Gland Gland H0075 Human Activated T-Cells Activated T-Cells Blood Cell Line Uni-ZAP XR (II) H0081 Human Fetal Epithelium Human Fetal Skin Skin Uni-ZAP XR (Skin) H0082 Human Fetal Muscle Human Fetal Muscle Sk Muscle Uni-ZAP XR H0083 HUMAN JURKAT Jurkat Cells Uni-ZAP XR MEMBRANE BOUND POLYSOMES H0085 Human Colon Human Colon Lambda ZAP II H0086 Human epithelioid Epithelioid Sarcoma, Sk Muscle disease Uni-ZAP XR sarcoma muscle H0087 Human Thymus Human Thymus pBluescript H0090 Human T-Cell Lymphoma T-Cell Lymphoma T-Cell disease Uni-ZAP XR H0095 Human Greater Omentum Human Greater Omentum peritoneum Uni-ZAP XR RNA Remake H0098 Human Adult Liver, Human Adult Liver Liver Uni-ZAP XR subtracted H0099 Human Lung Cancer, Human Lung Cancer Lung pBluescript subtracted H0100 Human Whole Six Week Human Whole Six Week Embryo Uni-ZAP XR Old Embryo Old Embryo H0101 Human 7 Weeks Old Human Whole 7 Week Embryo Lambda ZAP II Embryo, subtracted Old Embryo H0102 Human Whole 6 Week Human Whole Six Week Embryo pBluescript Old Embryo (II), subt Old Embryo H0107 Human Infant Adrenal Human Infant Adrenal Adrenal gland pBluescript Gland, subtracted Gland H0109 Human Macrophage, Macrophage Blood Cell Line pBluescript subtracted H0111 Human Placenta, Human Placenta Placenta pBluescript subtracted H0121 Human Cornea, subtracted Human Cornea eye Uni-ZAP XR H0122 Human Adult Skeletal Human Skeletal Muscle Sk Muscle Uni-ZAP XR Muscle H0123 Human Fetal Dura Mater Human Fetal Dura Mater Brain Uni-ZAP XR H0124 Human Human Sk Muscle disease Uni-ZAP XR Rhabdomyosarcoma Rhabdomyosarcoma H0125 Cem cells cyclohexamide Cyclohexamide Treated Blood Cell Line Uni-ZAP XR treated Cem, Jurkat, Raji, and Supt H0129 Jurkatcells, thiouridine Jurkat Cells Uni-ZAP XR activated, fract II H0130 LNCAP untreated LNCAP Cell Line Prostate Cell Line Uni-ZAP XR H0131 LNCAP + o.3 nM R1881 LNCAP Cell Line Prostate Cell Line Uni-ZAP XR H0132 LNCAP + 30 nM R1881 LNCAP Cell Line Prostate Cell Line Uni-ZAP XR H0134 Raji Cells, cyclohexamide Cyclohexamide Treated Blood Cell Line Uni-ZAP XR treated Cem, Jurkat, Raji, and Supt H0135 Human Synovial Sarcoma Human Synovial Sarcoma Synovium Uni-ZAP XR H0136 Supt Cells, cyclohexamide Cyclohexamide Treated Blood Cell Line Uni-ZAP XR treated Cem, Jurkat, Raji, and Supt H0140 Activated T-Cells, 8 hrs. Activated T-Cells Blood Cell Line Uni-ZAP XR H0141 Activated T-Cells, 12 hrs. Activated T-Cells Blood Cell Line Uni-ZAP XR H0144 Nine Week Old Early 9 Wk Old Early Stage Embryo Uni-ZAP XR Stage Human Human H0147 Human Adult Liver Human Adult Liver Liver Uni-ZAP XR H0149 7 Week Old Early Stage Human Whole 7 Week Embryo Uni-ZAP XR Human, subtracted Old Embryo H0150 Human Epididymus Epididymis Testis Uni-ZAP XR H0151 Early Stage Human Liver Human Fetal Liver Liver Uni-ZAP XR H0154 Human Fibrosarcoma Human Skin Fibrosarcoma Skin disease Uni-ZAP XR H0156 Human Adrenal Gland Human Adrenal Gland Adrenal Gland disease Uni-ZAP XR Tumor Tumor H0159 Activated T-Cells, 8 hrs., Activated T-Cells Blood Cell Line Uni-ZAP XR ligation 2 H0163 Human Synovium Human Synovium Synovium Uni-ZAP XR H0165 Human Prostate Cancer, Human Prostate Cancer, Prostate disease Uni-ZAP XR Stage B2 stage B2 H0166 Human Prostate Cancer, Human Prostate Cancer, Prostate disease Uni-ZAP XR Stage B2 fraction stage B2 H0167 Activated T-Cells, 24 hrs. Activated T-Cells Blood Cell Line Uni-ZAP XR H0169 Human Prostate Cancer, Human Prostate Cancer, Prostate disease Uni-ZAP XR Stage C fraction stage C H0170 12 Week Old Early Stage Twelve Week Old Early Embryo Uni-ZAP XR Human Stage Human H0171 12 Week Old Early Stage Twelve Week Old Early Embryo Uni-ZAP XR Human, II Stage Human H0172 Human Fetal Brain, Human Fetal Brain Brain Lambda ZAP II random primed H0173 Human Cardiomyopathy, Human Cardiomyopathy Heart disease Uni-ZAP XR RNA remake H0177 CAMA1Ee Cell Line CAMA1Ee Cell Line Breast Cell Line Uni-ZAP XR H0178 Human Fetal Brain Human Fetal Brain Brain Uni-ZAP XR H0179 Human Neutrophil Human Neutrophil Blood Cell Line Uni-ZAP XR H0181 Human Primary Breast Human Primary Breast Breast disease Uni-ZAP XR Cancer Cancer H0182 Human Primary Breast Human Primary Breast Breast disease Uni-ZAP XR Cancer Cancer H0183 Human Colon Cancer Human Colon Cancer Colon disease Uni-ZAP XR H0187 Resting T-Cell T-Cells Blood Cell Line Lambda ZAP II H0188 Human Normal Breast Human Normal Breast Breast Uni-ZAP XR H0190 Human Activated Human Blood Cell Line Uni-ZAP XR Macrophage (LPS) Macrophage/Monocytes H0191 Human Activated Human Blood Cell Line Uni-ZAP XR Macrophage (LPS), thiour Macrophage/Monocytes H0194 Human Cerebellum, Human Cerebellum Brain pBluescript subtracted H0196 Human Cardiomyopathy, Human Cardiomyopathy Heart Uni-ZAP XR subtracted H0197 Human Fetal Liver, Human Fetal Liver Liver Uni-ZAP XR subtracted H0199 Human Fetal Liver, Human Fetal Liver Liver Uni-ZAP XR subtracted, neg clone H0200 Human Greater Omentum, Human Greater Omentum peritoneum Uni-ZAP XR fract II remake, H0201 Human Hippocampus, Human Hippocampus Brain pBluescript subtracted H0202 Jurkat Cells, Cyclohexamide Treated Blood Cell Line Uni-ZAP XR cyclohexamide treated, Cem, Jurkat, Raji, and subtraction Supt H0204 Human Colon Cancer, Human Colon Cancer Colon pBluescript subtracted H0205 Human Colon Cancer, Human Colon Cancer Colon pBluescript differential H0208 Early Stage Human Lung, Human Fetal Lung Lung pBluescript subtracted H0209 Human Cerebellum, Human Cerebellum Brain Uni-ZAP XR differentially expressed H0211 Human Human Prostate Prostate pBluescript Prostate, differential expression H0212 Human Prostate, Human Prostate Prostate pBluescript subtracted H0213 Human Pituitary, Human Pituitary Uni-ZAP XR subtracted H0216 Supt cells, cyclohexamide Cyclohexamide Treated Blood Cell Line pBluescript treated, subtracted Cem, Jurkat, Raji, and Supt H0218 Activated T-Cells, 0 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XR subtracted H0219 Activated T-Cells, 0 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XR differentially expressed H0220 Activated T-Cells, 4 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XR subtracted H0222 Activated T-Cells, 8 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XR subtracted H0225 Activated T-Cells, 12 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XR differentially expressed H0229 Early Stage Human Brain, Early Stage Human Brain Brain Lambda ZAP II random primed H0230 Human Cardiomyopathy, Human Cardiomyopathy Heart disease Uni-ZAP XR diff exp H0231 Human Colon, subtraction Human Colon pBluescript H0234 human colon cancer, Human Colon Cancer, Liver pBluescript metastatic to liver, metasticized to liver differentially expressed H0235 Human colon cancer, Human Colon Cancer, Liver pBluescript metaticized to liver, metasticized to liver subtraction H0239 Human Kidney Tumor Human Kidney Tumor Kidney disease Uni-ZAP XR H0241 C7MCF7 cell line, C7MCF7 Cell Line, Breast Cell Line Uni-ZAP XR estrogen treated, estrogen treated subtraction H0242 Human Fetal Heart, Human Fetal Heart Heart pBluescript Differential (Fetal- Specific) H0244 Human 8 Week Whole Human 8 Week Old Embryo Uni-ZAP XR Embryo, subtracted Embryo H0246 Human Fetal Liver- Human Fetal Liver Liver Uni-ZAP XR Enzyme subtraction H0247 Human Membrane Bound Human Membrane Bound Blood Cell Line Uni-ZAP XR Polysomes-Enzyme Polysomes Subtraction H0249 HE7, subtracted by Human Whole 7 Week Embryo Uni-ZAP XR hybridization with E7 Old Embryo cDNA H0250 Human Activated Human Monocytes Uni-ZAP XR Monocytes H0251 Human Chondrosarcoma Human Chondrosarcoma Cartilage disease Uni-ZAP XR H0252 Human Osteosarcoma Human Osteosarcoma Bone disease Uni-ZAP XR H0253 Human adult testis, large Human Adult Testis Testis Uni-ZAP XR inserts H0254 Breast Lymph node cDNA Breast Lymph Node Lymph Node Uni-ZAP XR library H0255 breast lymph node CDNA Breast Lymph Node Lymph Node Lambda ZAP II library H0256 HL-60, unstimulated Human HL-60 Cells, Blood Cell Line Uni-ZAP XR unstimulated H0257 HL-60, PMA 4 H HL-60 Cells, PMA Blood Cell Line Uni-ZAP XR stimulated 4 H H0261 H. cerebellum, Enzyme Human Cerebellum Brain Uni-ZAP XR subtracted H0263 human colon cancer Human Colon Cancer Colon disease Lambda ZAP II H0264 human tonsils Human Tonsil Tonsil Uni-ZAP XR H0265 Activated T-Cell T-Cells Blood Cell Line Uni-ZAP XR (12 hs)/Thiouridine labelledEco H0266 Human Microvascular HMEC Vein Cell Line Lambda ZAP II Endothelial Cells, fract. A H0267 Human Microvascular HMEC Vein Cell Line Lambda ZAP II Endothelial Cells, fract. B H0268 Human Umbilical Vein HUVE Cells Umbilical vein Cell Line Lambda ZAP II Endothelial Cells, fract. A H0269 Human Umbilical Vein HUVE Cells Umbilical vein Cell Line Lambda ZAP II Endothelial Cells, fract. B H0270 HPAS (human pancreas, Human Pancreas Pancreas Uni-ZAP XR subtracted) H0271 Human Neutrophil, Human Neutrophil - Blood Cell Line Uni-ZAP XR Activated Activated H0272 HUMAN TONSILS, Human Tonsil Tonsil Uni-ZAP XR FRACTION 2 H0275 Human Infant Adrenal Human Infant Adrenal Adrenal gland pBluescript Gland, Subtracted Gland H0279 K562 cells K562 Cell line cell line Cell Line ZAP Express H0280 K562 + PMA (36 hrs) K562 Cell line cell line Cell Line ZAP Express H0284 Human OB MG63 control Human Osteoblastoma Bone Cell Line Uni-ZAP XR fraction I MG63 cell line H0286 Human OB MG63 treated Human Osteoblastoma Bone Cell Line Uni-ZAP XR (10 nM E2) fraction I MG63 cell line H0288 Human OB HOS control Human Osteoblastoma Bone Cell Line Uni-ZAP XR fraction I HOS cell line H0290 Human OB HOS treated Human Osteoblastoma Bone Cell Line Uni-ZAP XR (1 nM E2) fraction I HOS cell line H0292 Human OB HOS treated Human Osteoblastoma Bone Cell Line Uni-ZAP XR (10 nM E2) fraction I HOS cell line H0293 WI 38 cells Uni-ZAP XR H0294 Amniotic Cells - TNF Amniotic Cells - TNF Placenta Cell Line Uni-ZAP XR induced induced H0295 Amniotic Cells - Primary Amniotic Cells - Primary Placenta Cell Line Uni-ZAP XR Culture Culture H0300 CD34 positive cells (Cord CD34 Positive Cells Cord Blood ZAP Express Blood) H0305 CD34 positive cells (Cord CD34 Positive Cells Cord Blood ZAP Express Blood) H0306 CD34 depleted Buffy Coat CD34 Depleted Buffy Cord Blood ZAP Express (Cord Blood) Coat (Cord Blood) H0309 Human Chronic Synovitis Synovium, Chronic Synovium disease Uni-ZAP XR Synovitis/Osteoarthritis H0310 human caudate nucleus Brain Brain Uni-ZAP XR H0316 HUMAN STOMACH Human Stomach Stomach Uni-ZAP XR H0318 HUMAN B CELL Human B Cell Lymphoma Lymph Node disease Uni-ZAP XR LYMPHOMA H0327 human corpus colosum Human Corpus Callosum Brain Uni-ZAP XR H0328 human ovarian cancer Ovarian Cancer Ovary disease Uni-ZAP XR H0329 Dermatofibrosarcoma Dermatofibrosarcoma Skin disease Uni-ZAP XR Protuberance Protuberans H0331 Hepatocellular Tumor Hepatocellular Tumor Liver disease Lambda ZAP II H0333 Hemangiopericytoma Hemangiopericytoma Blood vessel disease Lambda ZAP II H0334 Kidney cancer Kidney Cancer Kidney disease Uni-ZAP XR H0339 Duodenum Duodenum Uni-ZAP XR H0340 Corpus Callosum Corpus Collosum-93052 Uni-ZAP XR H0341 Bone Marrow Cell Line Bone Marrow Cell Line Bone Marrow Cell Line Uni-ZAP XR (RS4; 11) RS4; 11 H0343 stomach cancer (human) Stomach Cancer - 5383A disease Uni-ZAP XR (human) H0344 Adipose tissue (human) Adipose - 6825A (human) Uni-ZAP XR H0345 SKIN Skin - 4000868H Skin Uni-ZAP XR H0346 Brain-medulloblastoma Brain (Medulloblastoma)- Brain disease Uni-ZAP XR 9405C006R H0349 human adult liver cDNA Human Adult Liver Liver pCMVSport 1 library H0350 Human Fetal Liver, mixed Human Fetal Liver, mixed Liver Uni-ZAP XR 10 & 14 week 10&14 Week H0351 Glioblastoma Glioblastoma Brain disease Uni-ZAP XR H0352 wilm''s tumor Wilm''s Tumor disease Uni-ZAP XR H0354 Human Leukocytes Human Leukocytes Blood Cell Line pCMVSport 1 H0355 Human Liver Human Liver, normal pCMVSport 1 Adult H0356 Human Kidney Human Kidney Kidney pCMVSport 1 H0357 H. Normalized Fetal Human Fetal Liver Liver Uni-ZAP XR Liver, II H0366 L428 cell line L428 ZAP Express H0369 H. Atrophic Endometrium Atrophic Endometrium Uni-ZAP XR and myometrium H0370 H. Lymph node breast Lymph node with Met. disease Uni-ZAP XR Cancer Breast Cancer H0373 Human Heart Human Adult Heart Heart pCMVSport 1 H0374 Human Brain Human Brain pCMVSport 1 H0375 Human Lung Human Lung pCMVSport 1 H0376 Human Spleen Human Adult Spleen Spleen pCMVSport 1 H0379 Human Tongue, frac 1 Human Tongue pSport1 H0380 Human Tongue, frac 2 Human Tongue pSport1 H0381 Bone Cancer Bone Cancer disease Uni-ZAP XR H0383 Human Prostate BPH, re- Human Prostate BPH Uni-ZAP XR excision H0388 Human Rejected Kidney, Human Rejected Kidney disease pBluescript 704 re-excision H0390 Human Amygdala Human Amygdala disease pBluescript Depression, re-excision Depression H0391 H. Meniingima, M6 Human Meningima brain pSport1 H0392 H. Meningima, M1 Human Meningima brain pSport1 H0393 Fetal Liver, subtraction II Human Fetal Liver Liver pBluescript H0395 A1-CELL LINE Redd-Sternberg cell ZAP Express H0399 Human Kidney Cortex, re- Human Kidney Cortex Lambda ZAP II rescue H0400 Human Striatum Human Brain, Striatum Brain Lambda ZAP II Depression, re-rescue Depression H0401 Human Pituitary, Human Pituitary pBluescript subtracted V H0402 CD34 depleted Buffy Coat CD34 Depleted Buffy Cord Blood ZAP Express (Cord Blood), re-excision Coat (Cord Blood) H0403 H. Umbilical Vein HUVE Cells Umbilical vein Cell Line Uni-ZAP XR Endothelial Cells, IL4 induced H0405 Human Pituitary, Human Pituitary pBluescript subtracted VI H0406 H Amygdala Depression, Human Amygdala Uni-ZAP XR subtracted Depression H0408 Human kidney Cortex, Human Kidney Cortex pBluescript subtracted H0409 H. Striatum Depression, Human Brain, Striatum Brain pBluescript subtracted Depression H0411 H Female Bladder, Adult Human Female Adult Bladder pSport1 Bladder H0412 Human umbilical vein HUVE Cells Umbilical vein Cell Line pSport1 endothelial cells, IL-4 induced H0413 Human Umbilical Vein HUVE Cells Umbilical vein Cell Line pSport1 Endothelial Cells, uninduced H0414 Ovarian Tumor I, OV5232 Ovarian Tumor, OV5232 Ovary disease pSport1 H0415 H. Ovarian Tumor, II, Ovarian Tumor, OV5232 Ovary disease pCMVSport 2.0 OV5232 H0416 Human Neutrophils, Human Neutrophil - Blood Cell Line pBluescript Activated, re-excision Activated H0417 Human Pituitary, Human Pituitary pBluescript subtracted VIII H0419 Bone Cancer, re-excision Bone Cancer Uni-ZAP XR H0421 Human Bone Marrow, re- Bone Marrow pBluescript excision H0422 T-Cell PHA 16 hrs T-Cells Blood Cell Line pSport1 H0423 T-Cell PHA 24 hrs T-Cells Blood Cell Line pSport1 H0424 Human Pituitary, subt IX Human Pituitary pBluescript H0427 Human Adipose Human Adipose, left pSport1 hiplipoma H0428 Human Ovary Human Ovary Tumor Ovary pSport1 H0429 K562 + PMA (36 hrs), re- K562 Cell line cell line Cell Line ZAP Express excision H0431 H. Kidney Medulla, re- Kidney medulla Kidney pBluescript excision H0433 Human Umbilical Vein HUVE Cells Umbilical vein Cell Line pBluescript Endothelial cells, frac B, re-excision H0435 Ovarian Tumor 10-3-95 Ovarian Tumor, Ovary pCMVSport 2.0 OV350721 H0436 Resting T-Cell Library, II T-Cells Blood Cell Line pSport1 H0437 H Umbilical Vein HUVE Cells Umbilical vein Cell Line Lambda ZAP II Endothelial Cells, frac A, re-excision H0438 H. Whole Brain #2, re- Human Whole Brain #2 ZAP Express excision H0439 Human Eosinophils Eosinophils pBluescript H0441 H. Kidney Cortex, Kidney cortex Kidney pBluescript subtracted H0443 H. Adipose, subtracted Human Adipose, left pSport1 hiplipoma H0444 Spleen metastic melanoma Spleen, Metastic Spleen disease pSport1 malignant melanoma H0445 Spleen, Chronic Human Spleen, CLL Spleen disease pSport1 lymphocytic leukemia H0449 CD34+ cell, I CD34 positive cells pSport1 H0450 CD34+cells, II CD34 positive cells pCMVSport 2.0 H0453 H. Kidney Pyramid, Kidney pyramids Kidney pBluescript subtracted H0455 H. Striatum Depression, Human Brain, Striatum Brain pBluescript subt Depression H0457 Human Eosinophils Human Eosinophils pSport1 H0458 CD34+ cell, I, frac II CD34 positive cells pSport1 H0459 CD34+cells, II, CD34 positive cells pCMVSport 2.0 FRACTION 2 H0461 H. Kidney Medulla, Kidney medulla Kidney pBluescript subtracted H0477 Human Tonsil, Lib 3 Human Tonsil Tonsil pSport1 H0478 Salivary Gland, Lib 2 Human Salivary Gland Salivary gland pSport1 H0479 Salivary Gland, Lib 3 Human Salivary Gland Salivary gland pSport1 H0483 Breast Cancer cell line, Breast Cancer Cell line, pSport1 MDA 36 MDA 36 H0484 Breast Cancer Cell line, Breast Cancer Cell line, pSport1 angiogenic Angiogenic, 36T3 H0485 Hodgkin''s Lymphoma I Hodgkin''s Lymphoma I disease pCMVSport 2.0 H0486 Hodgkin''s Lymphoma II Hodgkin''s Lymphoma II disease pCMVSport 2.0 H0487 Human Tonsils, lib I Human Tonsils pCMVSport 2.0 H0488 Human Tonsils, Lib 2 Human Tonsils pCMVSport 2.0 H0492 HL-60, RA 4 h, Subtracted HL-60 Cells, RA Blood Cell Line Uni-ZAP XR stimulated for 4 H H0494 Keratinocyte Keratinocyte pCMVSport 2.0 H0497 HEL cell line HEL cell line HEL pSport1 92.1.7 H0505 Human Astrocyte Human Astrocyte pSport1 H0506 Ulcerative Colitis Colon Colon pSport1 H0509 Liver, Hepatoma Human Liver, Hepatoma, Liver disease pCMVSport 3.0 patient 8 H0510 Human Liver, normal Human Liver, normal, Liver pCMVSport 3.0 Patient # 8 H0518 pBMC stimulated w/ poly pBMC stimulated with pCMVSport 3.0 I/C poly I/C H0519 NTERA2, control NTERA2, pCMVSport 3.0 Teratocarcinoma cell line H0520 NTERA2 + retinoic acid, NTERA2, pSport1 14 days Teratocarcinoma cell line H0521 Primary Dendritic Cells, Primary Dendritic cells pCMVSport 3.0 lib 1 H0522 Primary Dendritic Primary Dendritic cells pCMVSport 3.0 cells, frac 2 H0525 PCR, pBMC I/C treated pBMC stimulated with PCRII poly I/C H0528 Poly[I]/Poly[C] Normal Poly[I]/Poly[C] Normal pCMVSport 3.0 Lung Fibroblasts Lung Fibroblasts H0529 Myoloid Progenitor Cell TF-1 Cell Line; Myoloid pCMVSport 3.0 Line progenitor cell line H0530 Human Dermal Human Dermal pSport1 Endothelial Endothelial Cells; Cells, untreated untreated H0535 Human ovary tumor cell Ovarian Tumor, Ovary disease pSport1 OV350721 OV350721 H0538 Merkel Cells Merkel cells Lymph node pSport1 H0539 Pancreas Islet Cell Tumor Pancreas Islet Cell Pancreas disease pSport1 Tumour H0540 Skin, burned Skin, leg burned Skin pSport1 H0542 T Cell helper I Helper T cell pCMVSport 3.0 H0543 T cell helper II Helper T cell pCMVSport 3.0 H0544 Human endometrial Human endometrial pCMVSport 3.0 stromal cells stromal cells H0545 Human endometrial Human endometrial pCMVSport 3.0 stromal cells-treated with stromal cells-treated with progesterone proge H0546 Human endometrial Human endometrial pCMVSport 3.0 stromal cells-treated with stromal cells-treated with estradiol estra H0547 NTERA2 teratocarcinoma NTERA2, pSport1 cell line + retinoic acid (14 Teratocarcinoma cell line days) H0549 H. Epididiymus, caput & Human Epididiymus, Uni-ZAP XR corpus caput and corpus H0550 H. Epididiymus, cauda Human Epididiymus, Uni-ZAP XR cauda H0551 Human Thymus Stromal Human Thymus Stromal pCMVSport 3.0 Cells Cells H0553 Human Placenta Human Placenta pCMVSport 3.0 H0555 Rejected Kidney, lib 4 Human Rejected Kidney Kidney disease pCMVSport 3.0 H0556 Activated T- T-Cells Blood Cell Line Uni-ZAP XR cell(12 h)/Thiouridine-re- excision H0559 HL-60, PMA 4 H, re- HL-60 Cells, PMA Blood Cell Line Uni-ZAP XR excision stimulated 4 H H0560 KMH2 KMH2 pCMVSport 3.0 H0561 L428 L428 pCMVSport 3.0 H0563 Human Fetal Brain, Human Fetal Brain pCMVSport 2.0 normalized 50021F H0565 HUman Fetal Brain, Human Fetal Brain pCMVSport 2.0 normalized 100024F H0566 Human Fetal Human Fetal Brain pCMVSport 2.0 Brain, normalized c50F H0569 Human Fetal Brain, Human Fetal Brain pCMVSport 2.0 normalized CO H0570 Human Fetal Brain, Human Fetal Brain pCMVSport 2.0 normalized C500H H0571 Human Fetal Brain, Human Fetal Brain pCMVSport 2.0 normalized C500HE H0572 Human Fetal Brain, Human Fetal Brain pCMVSport 2.0 normalized AC5002 H0574 Hepatocellular Tumor; re- Hepatocellular Tumor Liver disease Lambda ZAP II excision H0575 Human Adult Human Adult Pulmonary Lung Uni-ZAP XR Pulmonary; re-excision H0576 Resting T-Cell; re- T-Cells Blood Cell Line Lambda ZAP II excision H0580 Dendritic cells, pooled Pooled dendritic cells pCMVSport 3.0 H0581 Human Bone Marrow, Human Bone Marrow Bone Marrow pCMVSport 3.0 treated H0583 B Cell lymphoma B Cell Lymphoma B Cell disease pCMVSport 3.0 H0584 Activated T-cells, 24 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XR re-excision H0585 Activated T-Cells, 12 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XR re-excision H0586 Healing groin wound, 6.5 healing groin wound, 6.5 groin disease pCMVSport 3.0 hours post incision hours post incision - 2/ H0587 Healing groin wound; 7.5 Groin-Feb. 19, 1997 groin disease pCMVSport 3.0 hours post incision H0589 CD34 positive cells (cord CD34 Positive Cells Cord Blood ZAP Express blood), re-ex H0590 Human adult small Human Adult Small Small Int. Uni-ZAP XR intestine, re-excision Intestine H0591 Human T-cell T-Cell Lymphoma T-Cell disease Uni-ZAP XR lymphoma; re-excision H0592 Healing groin wound - HGS wound healing disease pCMVSport 3.0 zero hr post-incision project; abdomen (control) H0593 Olfactory Olfactory epithelium from pCMVSport 3.0 epithelium; nasalcavity roof of left nasal cacit H0594 Human Lung Cancer; re- Human Lung Cancer Lung disease Lambda ZAP II excision H0595 Stomach cancer Stomach Cancer - 5383A disease Uni-ZAP XR (human); re-excision (human) H0596 Human Colon Cancer; re- Human Colon Cancer Colon Lambda ZAP II excision H0597 Human Colon; re-excision Human Colon Lambda ZAP II H0598 Human Stomach; re- Human Stomach Stomach Uni-ZAP XR excision H0599 Human Adult Heart; re- Human Adult Heart Heart Uni-ZAP XR excision H0600 Healing Abdomen Abdomen disease pCMVSport 3.0 wound; 70&90 min post incision H0601 Healing Abdomen Abdomen disease pCMVSport 3.0 Wound; 15 days post incision H0602 Healing Abdomen Abdomen disease pCMVSport 3.0 Wound; 21&29 days post incision H0604 Human Pituitary, re- Human Pituitary pBluescript excision H0606 Human Primary Breast Human Primary Breast Breast disease Uni-ZAP XR Cancer; re-excision Cancer H0607 H. Leukocytes, normalized H. Leukocytes pCMVSport 1 cot 50A3 H0609 H. Leukocytes, H. Leukocytes pCMVSport 1 normalized cot >500A H0611 H. Leukocytes, H. Leukocytes pCMVSport 1 normalized cot 500 B H0613 H. Leukocytes, normalized H. Leukocytes pCMVSport 1 cot 5B H0615 Human Ovarian Cancer Ovarian Cancer Ovary disease Uni-ZAP XR Reexcision H0616 Human Testes, Reexcision Human Testes Testis Uni-ZAP XR H0617 Human Primary Breast Human Primary Breast Breast disease Uni-ZAP XR Cancer Reexcision Cancer H0618 Human Adult Testes, Human Adult Testis Testis Uni-ZAP XR Large Inserts, Reexcision H0619 Fetal Heart Human Fetal Heart Heart Uni-ZAP XR H0620 Human Fetal Kidney; Human Fetal Kidney Kidney Uni-ZAP XR Reexcision H0622 Human Pancreas Tumor; Human Pancreas Tumor Pancreas disease Uni-ZAP XR Reexcision H0623 Human Umbilical Vein; Human Umbilical Vein Umbilical vein Uni-ZAP XR Reexcision Endothelial Cells H0624 12 Week Early Stage Twelve Week Old Early Embryo Uni-ZAP XR Human II; Reexcision Stage Human H0625 Ku 812F Basophils Line Ku 812F Basophils pSport1 H0626 Saos2 Cells; Untreated Saos2 Cell Line; pSport1 Untreated H0627 Saos2 Cells; Vitamin D3 Saos2 Cell Line; Vitamin pSport1 Treated D3 Treated H0628 Human Pre-Differentiated Human Pre-Differentiated Uni-ZAP XR Adipocytes Adipocytes H0630 Human Human Normalized pCMVSport 1 Leukocytes, normalized leukocyte control #4 H0631 Saos2, Dexamethosome Saos2 Cell Line; pSport1 Treated Dexamethosome Treated H0632 Hepatocellular Tumor; re- Hepatocellular Tumor Liver Lambda ZAP II excision H0633 Lung Carcinoma A549 TNFalpha activated A549- disease pSport1 TNFalpha activated Lung Carcinoma H0634 Human Testes Tumor, re- Human Testes Tumor Testis disease Uni-ZAP XR excision H0635 Human Activated T-Cells, Activated T-Cells Blood Cell Line Uni-ZAP XR re-excision H0637 Dendritic Cells From Dentritic cells from CD34 pSport1 CD34 Cells cells H0638 CD40 activated monocyte CD40 activated monocyte pSport1 dendridic cells dendridic cells H0640 Ficolled Human Stromal Ficolled Human Stromal Other Cells, Untreated Cells, Untreated H0641 LPS activated derived LPS activated monocyte pSport1 dendritic cells derived dendritic cells H0642 Hep G2 Cells, lambda Hep G2 Cells Other library H0643 Hep G2 Cells, PCR library Hep G2 Cells Other H0644 Human Placenta (re- Human Placenta Placenta Uni-ZAP XR excision) H0645 Fetal Heart, re-excision Human Fetal Heart Heart Uni-ZAP XR H0646 Lung, Cancer (4005313 Metastatic squamous cell pSport1 A3): Invasive Poorly lung carcinoma, poorly di Differentiated Lung Adenocarcinoma, H0647 Lung, Cancer (4005163 Invasive poorly disease pSport1 B7): Invasive, Poorly Diff. differentiated lung Adenocarcinoma, adenocarcinoma Metastatic H0648 Ovary, Cancer: (4004562 Papillary Cstic neoplasm disease pSport1 B6) Papillary Serous of low malignant potentia Cystic Neoplasm, Low Malignant Pot H0649 Lung, Normal: (4005313 Normal Lung pSport1 B1) H0650 B-Cells B-Cells pCMVSport 3.0 H0651 Ovary, Normal: Normal Ovary pSport1 (9805C040R) H0652 Lung, Normal: (4005313 Normal Lung pSport1 B1) H0653 Stromal Cells Stromal Cells pSport1 H0656 B-cells (unstimulated) B-cells (unstimulated) pSport1 H0657 B-cells (stimulated) B-cells (stimulated) PSport1 H0658 Ovary, Cancer 9809C332-Poorly Ovary & disease pSport1 (9809C332): Poorly differentiate Fallopian differentiated Tubes adenocarcinoma H0659 Ovary, Cancer Grade II Papillary Ovary disease pSport1 (15395A1F): Grade II Carcinoma, Ovary Papillary Carcinoma H0660 Ovary, Cancer: Poorly differentiated disease pSport1 (15799A1F) Poorly carcinoma, ovary differentiated carcinoma H0661 Breast, Cancer: (4004943 Breast cancer disease pSport1 A5) H0662 Breast, Normal: Normal Breast - Breast pSport1 (4005522B2) #4005522(B2) H0663 Breast, Cancer: (4005522 Breast Cancer - Breast disease pSport1 A2) #4005522(A2) H0664 Breast, Cancer: Breast Cancer Breast disease pSport1 (9806C012R) H0665 Stromal cells 3.88 Stromal cells 3.88 pSport H0666 Ovary, Cancer: (4004332 Ovarian Cancer, Sample disease pSport1 A2) #4004332A2 H0667 Stromal cells(HBM3.18) Stromal cell(HBM 3.18) pSport H0668 stromal cell clone 2.5 stromal cell clone 2.5 pSport1 H0670 Ovary, Cancer(4004650 Ovarian Cancer - pSport1 A3): Well-Differentiated 4004650A3 Micropapillary Serous Carcinoma H0671 Breast, Cancer: Breast Cancer-Sample # pSport1 (9802C02OE) 9802C02OE H0672 Ovary, Cancer: (4004576 Ovarian Ovary pSport1 A8) Cancer(4004576A8) H0673 Human Prostate Cancer, Human Prostate Cancer, Prostate Uni-ZAP XR Stage B2; re-excision stage B2 H0674 Human Prostate Cancer, Human Prostate Cancer, Prostate Uni-ZAP XR Stage C; re-excission stage C H0675 Colon, Cancer: Colon Cancer pCMVSport 3.0 (9808C064R) 9808C064R H0676 Colon, Cancer: Colon Cancer pCMVSport 3.0 (9808C064R)-total RNA 9808C064R H0677 TNFR degenerate oligo B-Cells PCRII H0682 Serous Papillary serous papillary pCMVSport 3.0 Adenocarcinoma adenocarcinoma (9606G304SPA3B) H0683 Ovarian Serous Papillary Serous papillary pCMVSport 3.0 Adenocarcinoma adenocarcinoma, stage 3C (9804G01 H0684 Serous Papillary Ovarian Cancer- Ovaries pCMVSport 3.0 Adenocarcinoma 9810G606 H0685 Adenocarcinoma of Adenocarcinoma of pCMVSport 3.0 Ovary, Human Cell Line, Ovary, Human Cell Line, # OVCAR-3 # OVCAR- H0686 Adenocarcinoma of Adenocarcinoma of pCMVSport 3.0 Ovary, Human Cell Line Ovary, Human Cell Line, # SW-626 H0687 Human normal Human normal Ovary pCMVSport 3.0 ovary(#9610G215) ovary(#9610G215) H0688 Human Ovarian Human Ovarian pCMVSport 3.0 Cancer(#9807G017) cancer(#9807G017), mRN A from Maura Ru H0689 Ovarian Cancer Ovarian Cancer, pCMVSport 3.0 #9806G019 H0690 Ovarian Cancer, # Ovarian Cancer, pCMVSport 3.0 9702G001 #9702G001 H0691 Normal Ovary, normal ovary, #9710G208 pCMVSport 3.0 #9710G208 H0692 BLyS Receptor from B Cell Lymphoma B Cell pCMVSport 3.0 Expression Cloning H0693 Normal Prostate Normal Prostate Tissue # pCMVSport 3.0 #ODQ3958EN ODQ3958EN H0694 Prostate gland Prostate gland, prostate gland pCMVSport 3.0 adenocarcinoma adenocarcinoma, mod/diff, gleason N0006 Human Fetal Brain Human Fetal Brain S0001 Brain frontal cortex Brain frontal cortex Brain Lambda ZAP II S0002 Monocyte activated Monocyte-activated blood Cell Line Uni-ZAP XR S0003 Human Osteoclastoma Osteoclastoma bone disease Uni-ZAP XR S0005 Heart Heart-left ventricle Heart pCDNA S0007 Early Stage Human Brain Human Fetal Brain Uni-ZAP XR S0010 Human Amygdala Amygdala Uni-ZAP XR S0011 STROMAL - Osteoclastoma bone disease Uni-ZAP XR OSTEOCLASTOMA S0013 Prostate Prostate prostate Uni-ZAP XR S0014 Kidney Cortex Kidney cortex Kidney Uni-ZAP XR S0015 Kidney medulla Kidney medulla Kidney Uni-ZAP XR S0016 Kidney Pyramids Kidney pyramids Kidney Uni-ZAP XR S0022 Human Osteoclastoma Osteoclastoma Stromal Uni-ZAP XR Stromal Cells - Cells unamplified S0024 Human Kidney Medulla - Human Kidney Medulla unamplified S0026 Stromal cell TF274 stromal cell Bone marrow Cell Line Uni-ZAP XR S0027 Smooth muscle, serum Smooth muscle Pulmanary Cell Line Uni-ZAP XR treated artery S0028 Smooth muscle, control Smooth muscle Pulmanary Cell Line Uni-ZAP XR artery S0029 brain stem Brain stem brain Uni-ZAP XR S0031 Spinal cord Spinal cord spinal cord Uni-ZAP XR S0032 Smooth muscle-ILb Smooth muscle Pulmanary Cell Line Uni-ZAP XR induced artery S0036 Human Substantia Nigra Human Substantia Nigra Uni-ZAP XR S0037 Smooth muscle, IL1b Smooth muscle Pulmanary Cell Line Uni-ZAP XR induced artery S0038 Human Whole Brain #2 - Human Whole Brain #2 ZAP Express Oligo dT >1.5 Kb S0039 Hypothalamus Hypothalamus Brain Uni-ZAP XR S0040 Adipocytes Human Adipocytes from Uni-ZAP XR Osteoclastoma S0042 Testes Human Testes ZAP Express S0044 Prostate BPH prostate BPH Prostate disease Uni-ZAP XR S0045 Endothelial cells-control Endothelial cell endothelial Cell Line Uni-ZAP XR cell-lung S0046 Endothelial-induced Endothelial cell endothelial Cell Line Uni-ZAP XR cell-lung S0049 Human Brain, Striatum Human Brain, Striatum Uni-ZAP XR S0050 Human Frontal Cortex, Human Frontal Cortex, disease Uni-ZAP XR Schizophrenia Schizophrenia S0051 Human Human Hypothalamus, disease Uni-ZAP XR Hypothalmus, Schizophrenia Schizophrenia S0052 neutrophils control human neutrophils blood Cell Line Uni-ZAP XR S0053 Neutrophils IL-1 and LPS human neutrophil induced blood Cell Line Uni-ZAP XR induced S0106 STRIATUM BRAIN disease Uni-ZAP XR DEPRESSION S0110 Brain Amygdala Brain disease Uni-ZAP XR Depression S0112 Hypothalamus Brain Uni-ZAP XR S0114 Anergic T-cell Anergic T-cell Cell Line Uni-ZAP XR S0116 Bone marrow Bone marrow Bone marrow Uni-ZAP XR S0118 Smooth muscle control 2 Smooth muscle Pulmanary Cell Line Uni-ZAP XR artery S0124 Smooth muscle-edited A Smooth muscle Pulmanary Cell Line Uni-ZAP XR artery S0126 Osteoblasts Osteoblasts Knee Cell Line Uni-ZAP XR S0132 Epithelial-TNFa and INF Airway Epithelial Uni-ZAP XR induced S0134 Apoptotic T-cell apoptotic cells Cell Line Uni-ZAP XR S0136 PERM TF274 stromal cell Bone marrow Cell Line Lambda ZAP II S0140 eosinophil-IL5 induced eosinophil lung Cell Line Uni-ZAP XR S0142 Macrophage-oxLDL macrophage-oxidized blood Cell Line Uni-ZAP XR LDL treated S0144 Macrophage (GM-CSF Macrophage (GM-CSF Uni-ZAP XR treated) treated) S0146 prostate-edited prostate BPH Prostate Uni-ZAP XR S0148 Normal Prostate Prostate prostate Uni-ZAP XR S0150 LNCAP prostate cell line LNCAP Cell Line Prostate Cell Line Uni-ZAP XR S0152 PC3 Prostate cell line PC3 prostate cell line Uni-ZAP XR S0174 Prostate-BPH subtracted II Human Prostate BPH pBluescript S0176 Prostate, normal, Prostate prostate Uni-ZAP XR subtraction I S0182 Human B Cell 8866 Human B-Cell 8866 Uni-ZAP XR S0188 Prostate, BPH, Lib 2 Human Prostate BPH disease pSport1 S0190 Prostate BPH, Lib 2, Human Prostate BPH pSport1 subtracted S0192 Synovial Fibroblasts Synovial Fibroblasts pSport1 (control) S0194 Synovial hypoxia Synovial Fibroblasts pSport1 S0196 Synovial IL-1/TNF Synovial Fibroblasts pSport1 stimulated S0206 Smooth Muscle-HASTE Smooth muscle Pulmanary Cell Line pBluescript normalized artery S0208 Messangial cell, frac 1 Messangial cell pSport1 S0210 Messangial cell, frac 2 Messangial cell pSport1 S0212 Bone Marrow Stromal Bone Marrow Stromal pSport1 Cell, untreated Cell, untreated S0214 Human Osteoclastoma, re- Osteoclastoma bone disease Uni-ZAP XR excision S0216 Neutrophils IL-1 and LPS human neutrophil induced blood Cell Line Uni-ZAP XR induced S0218 Apoptotic T-cell, re- apoptotic cells Cell Line Uni-ZAP XR excision S0220 H. hypothalamus, frac Hypothalamus Brain ZAP Express A; re-excision S0222 H. Frontal H. Brain, Frontal Cortex, Brain disease Uni-ZAP XR cortex, epileptic; re- Epileptic excision S0242 Synovial Fibroblasts Synovial Fibroblasts pSport1 (Il1/TNF), subt S0250 Human Osteoblasts II Human Osteoblasts Femur disease pCMVSport 2.0 S0260 Spinal Cord, re-excision Spinal cord spinal cord Uni-ZAP XR S0276 Synovial hypoxia-RSF Synovial fobroblasts Synovial tissue pSport1 subtracted (rheumatoid) S0278 H Macrophage (GM-CSF Macrophage (GM-CSF Uni-ZAP XR treated), re-excision treated) S0280 Human Adipose Tissue, Human Adipose Tissue Uni-ZAP XR re-excision S0282 Brain Frontal Cortex, re- Brain frontal cortex Brain Lambda ZAP II excision S0292 Osteoarthritis (OA-4) Human Osteoarthritic Bone disease pSport1 Cartilage S0294 Larynx tumor Larynx tumor Larynx, vocal disease pSport1 cord S0296 Normal lung Normal lung Lung pSport1 S0298 Bone marrow Bone marrow Bone marrow pSport1 stroma, treated stroma, treatedSB S0300 Frontal lobe, dementia; re- Frontal Lobe Brain Uni-ZAP XR excision dementia/Alzheimer''s S0306 Larynx normal #10 261-273 Larynx normal pSport1 S0308 Spleen/normal Spleen normal pSport1 S0310 Normal trachea Normal trachea pSport1 S0312 Human Human osteoarthritic disease pSport1 osteoarthritic; fraction II cartilage S0314 Human Human osteoarthritic disease pSport1 osteoarthritis; fraction I cartilage S0316 Human Normal Human Normal Cartilage pSport1 Cartilage, Fraction I S0318 Human Normal Cartilage Human Normal Cartilage pSport1 Fraction II S0322 Siebben Polyposis Siebben Polyposis pSport1 S0328 Palate carcinoma Palate carcinoma Uvula disease pSport1 S0330 Palate normal Palate normal Uvula pSport1 S0332 Pharynx carcinoma Pharynx carcinoma Hypopharynx pSport1 S0334 Human Normal Cartilage Human Normal Cartilage pSport1 Fraction III S0338 Human Osteoarthritic Human osteoarthritic disease pSport1 Cartilage Fraction III cartilage S0340 Human Osteoarthritic Human osteoarthritic disease pSport1 Cartilage Fraction IV cartilage S0342 Adipocytes; re-excision Human Adipocytes from Uni-ZAP XR Osteoclastoma S0344 Macrophage-oxLDL; re- macrophage-oxidized blood Cell Line Uni-ZAP XR excision LDL treated S0346 Human Amygdala; re- Amygdala Uni-ZAP XR excision S0348 Cheek Carcinoma Cheek Carcinoma disease pSport1 S0350 Pharynx Carcinoma Pharynx carcinoma Hypopharynx disease pSport1 S0352 Larynx Carcinoma Larynx carcinoma disease pSport1 S0354 Colon Normal II Colon Normal Colon pSport1 S0356 Colon Carcinoma Colon Carcinoma Colon disease pSport1 S0358 Colon Normal III Colon Normal Colon pSport1 S0360 Colon Tumor II Colon Tumor Colon disease pSport1 S0362 Human Gastrocnemius Gastrocnemius muscle pSport1 S0364 Human Quadriceps Quadriceps muscle pSport1 S0366 Human Soleus Soleus Muscle pSport1 S0370 Larynx carcinoma II Larynx carcinoma disease pSport1 S0372 Larynx carcinoma III Larynx carcinoma disease pSport1 S0374 Normal colon Normal colon pSport1 S0376 Colon Tumor Colon Tumor disease pSport1 S0378 Pancreas normal PCA4 Pancreas Normal PCA4 pSport1 No No S0380 Pancreas Tumor PCA4 Tu Pancreas Tumor PCA4 Tu disease pSport1 S0382 Larynx carcinoma IV Larynx carcinoma disease pSport1 S0384 Tongue carcinoma Tongue carcinoma disease pSport1 S0388 Human Human Hypothalamus, disease Uni-ZAP XR Hypothalamus, schizophrenia, Schizophrenia re-excision S0390 Smooth muscle, control; Smooth muscle Pulmanary Cell Line Uni-ZAP XR re-excision artery S0392 Salivary Gland Salivary gland; normal pSport1 S0394 Stomach; normal Stomach; normal pSport1 S0398 Testis; normal Testis; normal pSport1 S0404 Rectum normal Rectum, normal pSport1 S0406 Rectum tumour Rectum tumour pSport1 S0408 Colon, normal Colon, normal pSport1 S0410 Colon, tumour Colon, tumour pSport1 S0412 Temporal cortex- Temporal cortex, disease Other Alzheizmer; subtracted alzheimer S0414 Hippocampus, Alzheimer Hippocampus, Alzheimer Other Subtracted Subtracted S0418 CHME Cell Line; treated 5 hrs CHME Cell Line; treated pCMVSport 3.0 S0420 CHME Cell CHME Cell line, pSport1 Line, untreated untreatetd S0422 Mo7e Cell Line GM-CSF Mo7e Cell Line GM-CSF pCMVSport 3.0 treated (1 ng/ml) treated (1 ng/ml) S0424 TF-1 Cell Line GM-CSF TF-1 Cell Line GM-CSF pSport1 Treated Treated S0426 Monocyte activated; re- Monocyte-activated blood Cell Line Uni-ZAP XR excision S0428 Neutrophils control; re- human neutrophils blood Cell Line Uni-ZAP XR excision S0430 Aryepiglottis Normal Aryepiglottis Normal pSport1 S0432 Sinus piniformis Tumour Sinus piniformis Tumour pSport1 S0434 Stomach Normal Stomach Normal disease pSport1 S0436 Stomach Tumour Stomach Tumour disease pSport1 S0438 Liver Normal Met5No Liver Normal Met5No pSport1 S0440 Liver Tumour Met 5 Tu Liver Tumour pSport1 S0442 Colon Normal Colon Normal pSport1 S0444 Colon Tumor Colon Tumour disease pSport1 S0446 Tongue Tumour Tongue Tumour pSport1 S0448 Larynx Normal Larynx Normal pSport1 S0450 Larynx Tumour Larynx Tumour pSport1 S0452 Thymus Thymus pSport1 S0454 Placenta Placenta Placenta pSport1 S0456 Tongue Normal Tongue Normal pSport1 S0460 Thyroid Tumour Thyroid Tumour pSport1 S0462 Thyroid Thyroiditis Thyroid Thyroiditis pSport1 S0464 Larynx Normal Larynx Normal pSport1 S0468 Ea.hy.926 cell line Ea.hy.926 cell line pSport1 S0472 Lung Mesothelium PYBT pSport1 S0474 Human blood platelets Platelets Blood platelets Other S3012 Smooth Muscle Serum Smooth muscle Pulmanary Cell Line pBluescript Treated, Norm artery S3014 Smooth muscle, serum Smooth muscle Pulmanary Cell Line pBluescript induced, re-exc artery S6014 H. hypothalamus, frac A Hypothalamus Brain ZAP Express S6016 H. Frontal Cortex, H. Brain, Frontal Cortex, Brain disease Uni-ZAP XR Epileptic Epileptic S6022 H. Adipose Tissue Human Adipose Tissue Uni-ZAP XR S6024 Alzheimers, spongy Alzheimer''s/Spongy Brain disease Uni-ZAP XR change change S6026 Frontal Lobe, Dementia Frontal Lobe Brain Uni-ZAP XR dementia/Alzheimer''s S6028 Human Manic Depression Human Manic depression Brain disease Uni-ZAP XR Tissue tissue T0002 Activated T-cells Activated T-Cell, PBL Blood Cell Line pBluescript SK− fraction T0003 Human Fetal Lung Human Fetal Lung pBluescript SK− T0004 Human White Fat Human White Fat pBluescript SK− T0006 Human Pineal Gland Human Pinneal Gland pBluescript SK− T0008 Colorectal Tumor Colorectal Tumor disease pBluescript SK− T0010 Human Infant Brain Human Infant Brain Other T0023 Human Pancreatic Human Pancreatic disease pBluescript SK− Carcinoma Carcinoma T0039 HSA 172 Cells Human HSA172 cell line pBluescript SK− T0040 HSC172 cells SA172 Cells pBluescript SK− T0041 Jurkat T-cell G1 phase Jurkat T-cell pBluescript SK− T0042 Jurkat T-Cell, S phase Jurkat T-Cell Line pBluescript SK− T0048 Human Aortic Human Aortic pBluescript SK− Endothelium Endothilium T0049 Aorta endothelial cells + TNF-a Aorta endothelial cells pBluescript SK− T0060 Human White Adipose Human White Fat pBluescript SK− T0067 Human Thyroid Human Thyroid pBluescript SK− T0068 Normal Ovary, Normal Ovary, pBluescript SK− Premenopausal Premenopausal T0069 Human Uterus, normal Human Uterus, normal pBluescript SK− T0071 Human Bone Marrow Human Bone Marrow pBluescript SK− T0078 Human Liver, normal Human Liver, normal pBluescript SK− adult Adult T0082 Human Adult Retina Human Adult Retina pBluescript SK− T0104 HCC cell line metastisis to pBluescript SK− liver T0109 Human (HCC) cell line pBluescript SK− liver (mouse) metastasis, remake T0110 Human colon carcinoma pBluescript SK− (HCC) cell line, remake T0112 Human (Caco-2) cell line, pBluescript SK− adenocarcinoma, colon T0114 Human (Caco-2) cell line, pBluescript SK− adenocarcinoma, colon, remake T0115 Human Colon Carcinoma pBluescript SK− (HCC) cell line L0002 Atrium cDNA library Human heart L0005 Clontech human aorta polyA+ mRNA (#6572) L0021 Human adult (K. Okubo) L0022 Human adult lung 3″ directed MboI cDNA L0040 Human colon mucosa L0041 Human epidermal keratinocyte L0045 Human keratinocyte differential display (B. Lin) L0051 Human mRNA (Tripodis and Ragoussis) L0055 Human promyelocyte L0065 Liver HepG2 cell line. L0105 Human aorta polyA+ aorta (TFujiwara) L0109 Human brain cDNA brain L0138 Human normal gingiva normal gingiva L0142 Human placenta cDNA placenta (TFujiwara) L0143 Human placenta polyA+ placenta (TFujiwara) L0157 Human fetal brain brain (TFujiwara) L0158 Human fetal brain QBoqin brain L0163 Human heart cDNA heart (YNakamura) L0194 Human pancreatic cancer pancreatic cancer Patu 8988t cell line Patu 8988t L0351 Infant brain, Bento Soares BA, M13-derived L0352 Normalized infant brain, BA, M13-derived Bento Soares L0355 P, Human foetal Brain Bluescript Whole tissue L0361 Stratagene ovary ovary Bluescript SK (#937217) L0362 Stratagene ovarian cancer Bluescript SK− (#937219) L0363 NCI_CGAP_GC2 germ cell tumor Bluescript SK− L0364 NCI_CGAP_GC5 germ cell tumor Bluescript SK− L0366 Stratagene schizo brain schizophrenic brain S-11 Bluescript SK− S11 frontal lobe L0367 NCI_CGAP_Sch1 Schwannoma tumor Bluescript SK− L0368 NCI_CGAP_SS1 synovial sarcoma Bluescript SK− L0369 NCI_CGAP_AA1 adrenal adenoma adrenal gland Bluescript SK− L0371 NCI_CGAP_Br3 breast tumor breast Bluescript SK− L0372 NCI_CGAP_Co12 colon tumor colon Bluescript SK− L0373 NCI_CGAP_Co11 tumor colon Bluescript SK− L0374 NCI_CGAP_Co2 tumor colon Bluescript SK− L0375 NCI_CGAP_Kid6 kidney tumor kidney Bluescript SK− L0376 NCI_CGAP_Lar1 larynx larynx Bluescript SK− L0378 NCI_CGAP_Lu1 lung tumor lung Bluescript SK− L0381 NCI_CGAP_HN4 squamous cell carcinoma pharynx Bluescript SK− L0382 NCI_CGAP_Pr25 epithelium (cell line) prostate Bluescript SK− L0383 NCI_CGAP_Pr24 invasive tumor (cell line) prostate Bluescript SK− L0384 NCI_CGAP_Pr23 prostate tumor prostate Bluescript SK− L0386 NCI_CGAP_HN3 squamous cell carcinoma tongue Bluescript SK− from base of tongue L0387 NCI_CGAP_GCB0 germinal center B-cells tonsil Bluescript SK− L0388 NCI_CGAP_HN6 normal gingiva (cell line Bluescnpt SK− from immortalized kerati L0393 B, Human Liver tissue gt11 L0411 1-NIB Lafmid BA L0414 b4HB3MA Lafmid BA L0415 b4HB3MA Cot8-HAP-Ft Lafmid BA L0435 Infant brain, LLNL array lafmid BA of Dr. M. Soares 1NIB L0438 normalized infant brain total brain brain lafmid BA cDNA L0439 Soares infant brain 1NIB whole brain Lafmid BA L0442 4HB3MK Lafmid BK L0443 b4HB3MK Lafmid BK L0447 NHB3MK Lafmid BK L0448 3HFLSK20 Lafmid K L0455 Human retina cDNA retina eye lambda gt10 randomly primed sublibrary L0456 Human retina cDNA retina eye lambda gt10 Tsp509I-cleaved sublibrary L0457 multi-tissue normalized multi-tissue pooled lambda gt10 short-fragment L0462 WATM1 lambda gt11 L0471 Human fetal heart, Lambda ZAP Express Lambda ZAP Express L0475 KG1-a Lambda Zap KG1-a Lambda Zap Express Express cDNA library (Stratagene) L0480 Stratagene cat#937212 Lambda ZAP, (1992) pBluescript SK(−) L0481 CD34+DIRECTIONAL Lambda ZAPII L0483 Human pancreatic islet Lambda ZAPII L0485 STRATAGENE Human skeletal muscle leg muscle Lambda ZAPII skeletal muscle cDNA library, cat. #936215. L0493 NCI_CGAP_Ov26 papillary serous carcinoma ovary pAMP1 L0497 NCI_CGAP_HSC4 CD34+, CD38− from bone marrow pAMP1 normal bone marrow donor L0498 NCI_CGAP_HSC3 CD34+, T negative, bone marrow pAMP1 patient with chronic myelogenou L0500 NCI_CGAP_Brn20 oligodendroglioma brain pAMP1 L0502 NCI_CGAP_Br15 adenocarcinoma breast pAMP1 L0503 NCI_CGAP_Br17 adenocarcinoma breast pAMP1 L0506 NCI_CGAP_Br16 lobullar carcinoma in situ breast pAMP1 L0507 NCI_CGAP_Br14 normal epithelium breast pAMP1 L0512 NCI_CGAP_Ov36 borderline ovarian ovary pAMP1 carcinoma L0515 NCI_CGAP_Ov32 papillary serous carcinoma ovary pAMP1 L0517 NCI_CGAP_Pr1 pAMP10 L0518 NCI_CGAP_Pr2 pAMP10 L0519 NCI_CGAP_Pr3 pAMP10 L0520 NCI_CGAP_Alv1 alveolar pAMP10 rhabdomyosarcoma L0521 NCI_CGAP_Ew1 Ewing''s sarcoma pAMP10 L0522 NCI_CGAP_Kid1 kidney pAMP10 L0523 NCI_CGAP_Lip2 liposarcoma pAMP10 L0524 NCI_CGAP_Li1 liver pAMP10 L0525 NCI_CGAP_Li2 liver pAMP10 L0526 NCI_CGAP_Pr12 metastatic prostate bone pAMP10 lesion L0527 NCI_CGAP_Ov2 ovary pAMP10 L0528 NCI_CGAP_Pr5 prostate pAMP10 L0529 NCI_CGAP_Pr6 prostate pAMP10 L0530 NCI_CGAP_Pr8 prostate pAMP10 L0532 NCI_CGAP_Thy1 thyroid pAMP10 L0533 NCI_CGAP_HSC1 stem cells bone marrow pAMP10 L0534 Chromosome 7 Fetal brain brain pAMP10 Brain cDNA Library L0535 NCI_CGAP_Br5 infiltrating ductal breast pAMP10 carcinoma L0540 NCI_CGAP_Pr10 invasive prostate tumor prostate pAMP10 L0542 NCI_CGAP_Pr11 normal prostatic epithelial prostate pAMP10 cells L0543 NCI_CGAP_Pr9 normal prostatic epithelial prostate pAMP10 cells L0544 NCI_CGAP_Pr4 prostatic intraepithelial prostate pAMP10 neoplasia - high grade L0545 NCI_CGAP_Pr4.1 prostatic intraepithelial prostate pAMP10 neoplasia - high grade L0549 NCI_CGAP_HN10 carcinoma in situ from pAMP10 retromolar trigone L0550 NCI_CGAP_HN9 normal squamous pAMP10 epithelium from retromolar trigone L0551 NCI_CGAP_HN7 normal squamous pAMP10 epithelium, floor of mouth L0555 NCI_CGAP_Lu34 large cell carcinoma lung pAMP10 L0558 NCI_CGAP_Ov40 endometrioid ovarian ovary pAMP10 metastasis L0559 NCI_CGAP_Ov39 papillary serous ovarian ovary pAMP10 metastasis L0561 NCI_CGAP_HN11 normal squamous tongue pAMP10 epithelium L0562 Chromosome 7 HeLa HeLa pAMP10 cDNA Library cell line; ATCC L0563 Human Bone Marrow bone marrow pBluescript Stromal Fibroblast L0564 Jia bone marrow stroma bone marrow stroma pBluescript L0565 Normal Human Bone Hip pBluescript Trabecular Bone Cells L0581 Stratagene liver (#937224) liver pBluescript SK L0584 Stratagene cDNA library pBluescript SK(+) Human heart, cat#936208 L0586 HTCDL1 pBluescript SK(−) L0588 Stratagene endothelial cell pBluescript SK− 937223 L0589 Stratagene fetal retina pBluescript SK− 937202 L0590 Stratagene fibroblast pBluescript SK− (#937212) L0591 Stratagene HeLa cell s3 pBluescript SK− 937216 L0592 Stratagene hNT neuron pBluescript SK− (#937233) L0593 Stratagene pBluescript SK− neuroepithelium (#937231) L0594 Stratagene pBluescript SK− neuroepithelium NT2RAMI 937234 L0595 Stratagene NT2 neuronal neuroepithelial cells brain pBluescript SK− precursor 937230 L0596 Stratagene colon colon pBluescript SK− (#937204) L0597 Stratagene corneal stroma cornea pBluescript SK− (#937222) L0598 Morton Fetal Cochlea cochlea ear pBluescript SK− L0599 Stratagene lung (#937210) lung pBluescript SK− L0600 Weizmann Olfactory olfactory epithelium nose pBluescript SK− Epithelium L0601 Stratagene pancreas pancreas pBluescript SK− (#937208) L0602 Pancreatic Islet pancreatic islet pancreas pBluescript SK− L0603 Stratagene placenta placenta pBluescript SK− (#937225) L0604 Stratagene muscle 937209 muscle skeletal muscle pBluescript SK− L0605 Stratagene fetal spleen fetal spleen spleen pBluescript SK− (#937205) L0606 NCI_CGAP_Lym5 follicular lymphoma lymph node pBluescript SK− L0607 NCI_CGAP_Lym6 mantle cell lymphoma lymph node pBluescript SK− L0608 Stratagene lung carcinoma lung carcinoma lung NCI-H69 pBluescript SK− 937218 L0609 Schiller astrocytoma astrocytoma brain pBluescript SK− (Stratagene) L0611 Schiller meningioma meningioma brain pBluescript SK− (Stratagene) L0612 Schiller oligodendroglioma brain pBluescript SK− oligodendroglioma (Stratagene) L0615 22 week old human fetal pBluescriptII SK(−) liver cDNA library L0617 Chromosome 22 exon pBluescriptIIKS+ L0619 Chromosome 9 exon II pBluescriptIIKS+ L0622 HM1 pcDNAII (Invitrogen) L0623 HM3 pectoral muscle (after pcDNAII (Invitrogen) mastectomy) L0625 NCI_CGAP_AR1 bulk alveolar tumor pCMV-SPORT2 L0626 NCI_CGAP_GC1 bulk germ cell seminoma pCMV-SPORT2 L0627 NCI_CGAP_Co1 bulk tumor colon pCMV-SPORT2 L0628 NCI_CGAP_Ov1 ovary bulk tumor ovary pCMV-SPORT2 L0629 NCI_CGAP_Mel3 metastatic melanoma to bowel (skin pCMV-SPORT4 bowel primary) L0631 NCI_CGAP_Br7 breast pCMV-SPORT4 L0632 NCI_CGAP_Li5 hepatic adenoma liver pCMV-SPORT4 L0634 NCI_CGAP_Ov8 serous adenocarcinoma ovary pCMV-SPORT4 L0635 NCI_CGAP_PNS1 dorsal root ganglion peripheral pCMV-SPORT4 nervous system L0636 NCI_CGAP_Pit1 four pooled pituitary brain pCMV-SPORT6 adenomas L0637 NCI_CGAP_Brn53 three pooled meningiomas brain pCMV-SPORT6 L0638 NCI_CGAP_Brn35 tumor, 5 pooled (see brain pCMV-SPORT6 description) L0639 NCI_CGAP_Brn52 tumor, 5 pooled (see brain pCMV-SPORT6 description) L0640 NCI_CGAP_Br18 four pooled high-grade breast pCMV-SPORT6 tumors, including two prima L0641 NCI_CGAP_Co17 juvenile granulosa tumor colon pCMV-SPORT6 L0642 NCI_CGAP_Co18 moderately differentiated colon pCMV-SPORT6 adenocarcinoma L0643 NCI_CGAP_Co19 moderately differentiated colon pCMV-SPORT6 adenocarcinoma L0644 NCI_CGAP_Co20 moderately differentiated colon pCMV-SPORT6 adenocarcinoma L0645 NCI_CGAP_Co21 moderately differentiated colon pCMV-SPORT6 adenocarcinoma L0646 NCI_CGAP_Co14 moderately-differentiated colon pCMV-SPORT6 adenocarcinoma L0647 NCI_CGAP_Sar4 five pooled sarcomas, connective pCMV-SPORT6 including myxoid tissue liposarcoma L0648 NCI_CGAP_Eso2 squamous cell carcinoma esophagus pCMV-SPORT6 L0649 NCI_CGAP_GU1 2 pooled high-grade genitourinary pCMV-SPORT6 transitional cell tumors tract L0650 NCI_CGAP_Kid13 2 pooled Wilms'' tumors, kidney pCMV-SPORT6 one primary and one metast L0651 NCI_CGAP_Kid8 renal cell tumor kidney pCMV-SPORT6 L0652 NCI_CGAP_Lu27 four pooled poorly- lung pCMV-SPORT6 differentiated adenocarcinomas L0653 NCI_CGAP_Lu28 two pooled squamous cell lung pCMV-SPORT6 carcinomas L0654 NCI_CGAP_Lu31 lung, cell line pCMV-SPORT6 L0655 NCI_CGAP_Lym12 lymphoma, follicular lymph node pCMV-SPORT6 mixed small and large cell L0656 NCI_CGAP_Ov38 normal epithelium ovary pCMV-SPORT6 L0657 NCI_CGAP_Ov23 tumor, 5 pooled (see ovary pCMV-SPORT6 description) L0658 NCI_CGAP_Ov35 tumor, 5 pooled (see ovary pCMV-SPORT6 description) L0659 NCI_CGAP_Pan1 adenocarcinoma pancreas pCMV-SPORT6 L0661 NCI_CGAP_Mel15 malignant melanoma, skin pCMV-SPORT6 metastatic to lymph node L0662 NCI_CGAP_Gas4 poorly differentiated stomach pCMV-SPORT6 adenocarcinoma with signet r L0663 NCI_CGAP_Ut2 moderately-differentiated uterus pCMV-SPORT6 endometrial adenocarcino L0664 NCI_CGAP_Ut3 poorly-differentiated uterus pCMV-SPORT6 endometrial adenocarcinoma, L0665 NCI_CGAP_Ut4 serous papillary uterus pCMV-SPORT6 carcinoma, high grade, 2 pooled t L0666 NCI_CGAP_Ut1 well-differentiated uterus pCMV-SPORT6 endometrial adenocarcinoma, 7 L0667 NCI_CGAP_CML1 myeloid cells, 18 pooled whole blood pCMV-SPORT6 CML cases, BCR/ABL rearra L0669 Human MCF7 cDNA breast adenocarcinoma breast MCF7 pCR II [Invitrogen] subtracted with MDA- MB-231 cDNA L0684 Stanley Frontal SB pool 1 frontal lobe (see brain pCR2.1-TOPO description) (Invitrogen) L0686 Stanley Frontal SN pool 2 frontal lobe (see brain pCR2.1-TOPO description) (Invitrogen) L0698 Testis 2 PGEM 5zf(+) L0700 Outward Alu-primed pGEM-3Z hncDNA library L0710 NIH_MGC_7 small cell carcinoma lung MGC3 pOTB7 L0717 Gessler Wilms tumor pSPORT1 L0718 Testis 5 pSPORT1 L0731 Soares_pregnant_uterus_NbHPU uterus pT7T3-Pac L0738 Human colorectal cancer pT7T3D L0740 Soares melanocyte melanocyte pT7T3D (Pharmacia) 2NbHM with a modified polylinker L0741 Soares adult brain brain pT7T3D (Pharmacia) N2b4HB55Y with a modified polylinker L0742 Soares adult brain brain pT7T3D (Pharmacia) N2b5HB55Y with a modified polylinker L0743 Soares breast 2NbHBst breast pT7T3D (Pharmacia) with a modified polylinker L0744 Soares breast 3NbHBst breast pT7T3D (Pharmacia) with a modified polylinker L0745 Soares retina N2b4HR retina eye pT7T3D (Pharmacia) with a modified polylinker L0746 Soares retina N2b5HR retina eye pT7T3D (Pharmacia) with a modified polylinker L0747 Soares_fetal_heart_NbHH heart pT7T3D (Pharmacia) 19W with a modified polylinker L0748 Soares fetal liver spleen Liver and pT7T3D (Pharmacia) 1NFLS Spleen with a modified polylinker L0749 Soares_fetal_liver_spleen_1NFLS_S1 Liver and pT7T3D (Pharmacia) Spleen with a modified polylinker L0750 Soares_fetal_lung_NbHL19W lung pT7T3D (Pharmacia) with a modified polylinker L0751 Soares ovary tumor ovarian tumor ovary pT7T3D (Pharmacia) NbHOT with a modified polylinker L0752 Soares_parathyroid_tumor_NbHPA parathyroid tumor parathyroid pT7T3D (Pharmacia) gland with a modified polylinker L0753 Soares_pineal_gland_N3HPG pineal gland pT7T3D (Pharmacia) with a modified polylinker L0754 Soares placenta Nb2HP placenta pT7T3D (Pharmacia) with a modified polylinker L0755 Soares_placenta_8to9week_2NbHP8to9W placenta pT7T3D (Pharmacia) with a modified polylinker L0756 Soares_multiple_sclerosis_2NbHMSP multiple sclerosis lesions pT7T3D (Pharmacia) with a modified polylinker V_TYPE L0757 Soares_senescent_fibroblasts_NbHSF senescent fibroblast pT7T3D (Pharmacia) with a modified polylinker V_TYPE L0758 Soares_testis_NHT pT7T3D-Pac (Pharmacia) with a modified polylinker L0759 Soares_total_fetus_Nb2HF8_9w pT7T3D-Pac (Pharmacia) with a modified polylinker L0760 Barstead aorta HPLRB3 aorta pT7T3D-Pac (Pharmacia) with a modified polylinker L0761 NCI_CGAP_CLL1 B-cell, chronic lymphotic pT7T3D-Pac leukemia (Pharmacia) with a modified polylinker L0762 NCI_CGAP_Br1.1 breast pT7T3D-Pac (Pharmacia) with a modified polylinker L0763 NCI_CGAP_Br2 breast pT7T3D-Pac (Pharmacia) with a modified polylinker L0764 NCI_CGAP_Co3 colon pT7T3D-Pac (Pharmacia) with a modified polylinker L0765 NCI_CGAP_Co4 colon pT7T3D-Pac (Pharmacia) with a modified polylinker L0766 NCI_CGAP_GCB1 germinal center B cell pT7T3D-Pac (Pharmacia) with a modified polylinker L0767 NCI_CGAP_GC3 pooled germ cell tumors pT7T3D-Pac (Pharmacia) with a modified polylinker L0768 NCI_CGAP_GC4 pooled germ cell tumors pT7T3D-Pac (Pharmacia) with a modified polylinker L0769 NCI_CGAP_Brn25 anaplastic brain pT7T3D-Pac oligodendroglioma (Pharmacia) with a modified polylinker L0770 NCI_CGAP_Brn23 glioblastoma (pooled) brain pT7T3D-Pac (Pharmacia) with a modified polylinker L0771 NCI_CGAP_Co8 adenocarcinoma colon pT7T3D-Pac (Pharmacia) with a modified polylinker L0772 NCI_CGAP_Co10 colon tumor RER+ colon pT7T3D-Pac (Pharmacia) with a modified polylinker L0773 NCI_CGAP_Co9 colon tumor RBR+ colon pT7T3D-Pac (Pharmacia) with a modified polylinker L0774 NCI_CGAP_Kid3 kidney pT7T3D-Pac (Pharmacia) with a modified polylinker L0775 NCI_CGAP_Kid5 2 pooled tumors (clear cell kidney pT7T3D-Pac type) (Pharmacia) with a modified polylinker L0776 NCI_CGAP_Lu5 carcinoid lung pT7T3D-Pac (Pharmacia) with a modified polylinker L0777 Soares_NhHMPu_S1 Pooled human mixed (see pT7T3D-Pac melanocyte, fetal heart, below) (Pharmacia) with a and pregnant modified polylinker L0779 Soares_NFL_T_GBC_S1 pooled pT7T3D-Pac (Pharmacia) with a modified polylinker L0780 Soares_NSF_F8_9W_OT_PA_P_S1 pooled pT7T3D-Pac (Pharmacia) with a modified polylinker L0782 NCI_CGAP_Pr21 normal prostate prostate pT7T3D-Pac (Pharmacia) with a modified polylinker L0783 NCI_CGAP_Pr22 normal prostate prostate pT7T3D-Pac (Pharmacia) with a modified polylinker L0784 NCI_CGAP_Lei2 leiomyosarcoma soft tissue pT7T3D-Pac (Pharmacia) with a modified polylinker L0785 Barstead spleen HPLRB2 spleen pT7T3D-Pac (Pharmacia) with a modified polylinker L0786 Soares_NbHFB whole brain pT7T3D-Pac (Pharmacia) with a modified polylinker L0787 NCI_CGAP_Sub1 pT7T3D-Pac (Pharmacia) with a modified polylinker L0788 NCI_CGAP_Sub2 pT7T3D-Pac (Pharmacia) with a modified polylinker L0789 NCI_CGAP_Sub3 pT7T3D-Pac (Pharmacia) with a modified polylinker L0790 NCI_CGAP_Sub3 pT7T3D-Pac (Pharmacia) with a modified polylinker L0791 NCI_CGAP_Sub5 pT7T3D-Pac (Pharmacia) with a modified polylinker L0792 NCI_CGAP_Sub6 pT7T3D-Pac (Pharmacia) with a modified polylinker L0793 NCI_CGAP_Sub7 pT7T3D-Pac (Pharmacia) with a modified polylinker L0794 NCI_CGAP_GC6 pooled germ cell tumors pT7T3D-Pac (Pharmacia) with a modified polylinker L0796 NCI_CGAP_Brn50 medulloblastoma brain pT7T3D-Pac (Pharmacia) with a modified polylinker L0800 NCI_CGAP_Co16 colon tumor, RER+ colon pT7T3D-Pac (Pharmacia) with a modified polylinker L0803 NCI_CGAP_Kid11 kidney pT7T3D-Pac (Pharmacia) with a modified polylinker L0804 NCI_CGAP_Kid12 2 pooled tumors (clear cell kidney pT7T3D-Pac type) (Pharmacia) with a modified polylinker L0805 NCI_CGAP_Lu24 carcinoid lung pT7T3D-Pac (Pharmacia) with a modified polylinker L0806 NCI_CGAP_Lu19 squamous cell carcinoma, lung pT7T3D-Pac poorly differentiated (4 (Pharmacia) with a modified polylinker L0807 NCI_CGAP_Ov18 fibrotheoma ovary pT7T3D-Pac (Pharmacia) with a modified polylinker L0809 NCI_CGAP_Pr28 prostate pT7T3D-Pac (Pharmacia) with a modified polylinker L1562 CN0027 colon_normal puc18 L2251 Human fetal lung Fetal lung L2252 Human placenta placenta L2255 GLC corresponding non pBluescript sk(−) cancerous liver tissue L2257 NIH_MGC_65 adenocarcinoma colon pCMV-SPORT6 L2258 NIH_MGC_67 retinoblastoma eye pCMV-SPORT6 L2259 NIH_MGC_68 large cell carcinoma lung pCMV-SPORT6 L2260 NIH_MGC_69 large cell carcinoma, lung pCMV-SPORT6 undifferentiated L2261 NIH_MGC_70 epithelioid carcinoma pancreas pCMV-SPORT6 L2262 NIH_MGC_72 melanotic melanoma skin pCMV-SPORT6 L2263 NIH_MGC_66 adenocarcinoma ovary pCMV-SPORT6 L2264 NIH_MGC_71 leiomyosarcoma uterus pCMV-SPORT6 L2265 NIH_MGC_39 adenocarcinoma pancreas pOTB7 L2270 Lupski_dorsal_root_ganglion dorsal root ganglia pCMV-SPORT6 (Life Technologies) L2293 BT0762 breast puc18 L2300 BT0789 breast puc18 L2336 CT0428 colon puc18 L2359 UT0023 uterus_tumor puc18 L2368 UT0041 uterus_tumor puc18 L2482 HT0497 head_neck puc18 L2486 HT0527 head_neck puc18 L2491 HT0559 head_neck puc18 L2497 HT0618 head_neck puc18 L2499 HT0622 head_neck puc18 L2504 HT0636 head_neck puc18 L2528 HT0713 head_neck puc18 L2630 HT0865 head_neck puc18 L2647 HT0894 head_neck puc18 L2652 NIH_MGC_57 glioblastoma brain pDNR-LIB (Clontech) L2653 NIH_MGC_58 hypernephroma kidney pDNR-LIB (Clontech) L2654 NIH_MGC_9 adenocarcinoma cell line ovary pOTB7 L2655 NIH_MGC_55 from acute myelogenous bone marrow pDNR-LIB (Clontech) leukemia L2657 NIH_MGC_54 from chronic myelogenous bone marrow pDNR-LIB (Clontech) leukemia L2669 NT0022 nervous_tumor puc18 L2670 NT0023 nervous_tumor puc18 L2744 FT0004 prostate_tumor puc18 L2759 FT0028 prostate_tumor puc18 L2879 AN0032 amnion_normal puc18 L2904 BN0042 breast_normal puc18 L2906 BN0047 breast_normal puc18 L2909 BN0067 breast_normal puc18 L2910 BN0070 breast_normal puc18 L3109 ET0046 lung_tumor puc18 L3181 MT0107 marrow puc18 L3215 OT0083 ovary puc18 L3271 FN0094 prostate_normal puc18 L3311 FN0180 prostate_normal puc18 L3378 TN0080 testis_normal puc18 L3387 GKB hepatocellular carcinoma pBluescript sk(−) L3388 GKC hepatocellular carcinoma pBluescript sk(−) L3391 NIH_MGC_53 carcinoma, cell line bladder pDNR-LIB (Clontech) L3485 GN0070 placenta_normal puc18 L3499 HT0617 head_neck puc18 L3503 HT0870 head_neck puc18 L3576 TN0086 testis_normal puc18 L3643 ADB Adrenal gland pBluescript sk(−) L3644 ADC Adrenal gland pBluescript sk(−) L3645 Cu adrenal cortico adenoma pBluescript sk(−) for Cushing''s syndrome L3646 DCA pTriplEx2 L3649 DCB pTriplEx2 L3651 FHTA hypothalamus pTriplEx2 L3652 FHTB hypothalamus pTriplEx2 L3653 HTB Hypothalamus pBluescript sk(−) L3655 HTC Hypothalamus pBluescript sk(−) L3658 cdA pheochromocytoma pTriplEx2 L3659 CB cord blood pBluescript L3663 NIH_MGC_60 adenocarcinoma prostate pDNR-LIB (Clontech) L3665 NIH_MGC_75 kidney pDNR-LIB (Clontech) L3709 CT0515 colon puc18 L3726 GN0038 placenta_normal puc18 L3811 NPC pituitary pBluescript sk(−) L3812 NPD pituitary pBluescript sk(−) L3814 BM Bone marrow pTriplEx2 L3815 MDS Bone marrow pTriplEx2 L3816 HEMBA1 whole embryo, mainly pME18SFL3 head L3817 HEMBB1 whole embryo, mainly pME18SFL3 body L3818 MAMMA1 mammary gland pME18SFL3 L3822 NIH_MGC_59 mucoepidermoid lung pDNR-LIB (Clontech) carcinoma L3824 NT2RM2 NT2 pME18SFL3 L3825 NT2RM4 NT2 pME18SFL3 L3826 NT2RP1 NT2 pUC19FL3 L3827 NT2RP2 NT2 pME18SFL3 L3828 NT2RP3 NT2 pME18SFL3 L3829 NT2RP4 NT2 pME18SFL3 L3831 OVARC1 ovary, tumor tissue pME18SFL3 L3832 PLACE1 placenta pME18SFL3 L3833 PLACE2 placenta pME18SFL3 L3834 PLACE3 placenta pME18SFL3 L3872 NCI_CGAP_Skn1 skin, normal, 4 pCMV-SPORT6 pooled sa L3904 NCI_CGAP_Brn64 glioblastoma with EGFR brain pCMV-SPORT6 amplification L3905 NCI_CGAP_Brn67 anaplastic brain pCMV-SPORT6 oligodendroglioma with 1p/19q loss L4497 NCI_CGAP_Br22 invasive ductal carcinoma, breast pCMV-SPORT6 3 pooled samples L4501 NCI_CGAP_Sub8 pT7T3D-Pac (Pharmacia) with a modified polylinker L4556 NCI_CGAP_HN13 squamous cell carcinoma tongue pCMV-SPORT6 L4559 NCI_CGAP_Thy3 follicular carcinoma thyroid pCMV-SPORT6 L4560 NCI_CGAP_Ut7 tumor uterus pCMV-SPORT6 L4747 NCI_CGAP_Brn41 oligodendroglioma brain pT7T3D-Pac (Pharmacia) with a modified polylinker L5564 NCI_CGAP_HN20 normal pAMP1 head/neck tissue L5565 NCI_CGAP_Brn66 glioblastoma with brain pCMV-SPORT6 probably TP53 mutation and witho L5566 NCI_CGAP_Brn70 anaplastic brain pCMV-SPORT6.ccdb oligodendroglioma L5572 NCI_CGAP_Co27 adenocarcinoma colon pAMP1 (mucinous component) L5574 NCI_CGAP_HN19 normal epithelium nasopharynx pAMP10 L5575 NCI_CGAP_Brn65 glioblastoma without brain pCMV-SPORT6 EGFR amplification L5622 NCI_CGAP_Skn3 skin pCMV-SPORT6 L5623 NCI_CGAP_Skn4 squamous cell carcinoma skin pCMV-SPORT6 Description of Table 5

Table 5 provides a key to the OMIM reference identification numbers disclosed in Table 1B1, column 9. OMIM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM. McKusick-Nathan Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseases associated with the cytologic band disclosed in Table 1B.1, column 8, as determined using the Morbid Map database. TABLE 5 OMIM Reference Description 100710 Myasthenic syndrome, slow-channel congenital, 601462 101000 Meningioma, NF2-related, sporadic Schwannoma, sporadic 101000 Neurofibromatosis, type 2 101000 Neurolemmomatosis 101000 Malignant mesothelioma, sporadic 102200 Somatotrophinoma 102700 Severe combined immunodeficiency due to ADA deficiency 102700 Hemolytic anemia due to ADA excess 102770 Myoadenylate deaminase deficiency 103581 Albright hereditary osteodystrophy-2 103600 [Dysalbuminemic hyperthyroxinemia] 103600 [Dysalbuminemic hyperzincemia], 194470 103600 Analbuminemia 103950 Emphysema due to alpha-2-macroglobulin deficiency 104150 [AFP deficiency, congenital] 104150 [Hereditary persistence of alpha-fetoprotein] 104311 Alzheimer disease-3 104500 Amelogenesis imperfecta-2, hypoplastic local type 106100 Angioedema, hereditary 106150 Hypertension, essential, susceptibility to 106150 Preeclampsia, susceptibility to 106165 Hypertension, essential, 145500 106180 Myocardial infarction, susceptibility to 107250 Anterior segment mesenchymal dysgenesis 107300 Antithrombin III deficiency 107741 Hyperlipoproteinemia, type III 107777 Diabetes insipidus, nephrogenic, autosomal recessive, 222000 107970 Arrhythmogenic right ventricular dysplasia-1 108120 Distal arthrogryposis-1 108725 Atherosclerosis, susceptibility to 108730 Brody myopathy, 601003 108985 Atrophia areata 109150 Machado-Joseph disease 110100 Blepharophimosis, epicanthus inversus, and ptosis, type 1 112250 Bone dysplasia with medullary fibrosarcoma 112410 Hypertension with brachydactyly 113900 Heart block, progressive familial, type I 114240 Muscular dystrophy, limb-girdle, type 2A, 253600 114400 Lynch cancer family syndrome II 116806 Colorectal cancer 116860 Cavernous angiomatous malformations 117700 [Hypoceruloplasminemia, hereditary] 117700 Hemosiderosis, systemic, due to aceruloplasminemia 120280 Stickler syndrome, type III 120280 Marshall syndrome, 154780 120550 C1q deficiency, type A 120570 C1q deficiency, type B 120575 C1q deficiency, type C 120700 C3 deficiency 120950 C8 deficiency, type I 120960 C8 deficiency, type II 122720 Nicotine addiction, protection from 122720 Coumarin resistance, 122700 123000 Craniometaphyseal dysplasia 123270 [Creatine kinase, brain type, ectopic expression of] 123620 Cataract, cerulean, type 2, 601547 123940 White sponge nevus, 193900 126340 Xeroderma pigmentosum, group D, 278730 126391 DNA ligase I deficiency 126451 Schizophrenia, susceptibility to 126650 Chloride diarrhea, congenital, Finnish type, 214700 126650 Colon cancer 129900 EEC syndrome-1 130500 Elliptocytosis-1 131100 Multiple endocrine neoplasia I 131100 Prolactinoma, hyperparathyroidism, carcinoid syndrome 131100 Carcinoid tumor of lung 131210 Atherosclerosis, susceptibility to 133171 [Erythrocytosis, familial], 133100 133200 Erythrokeratodermia variabilis 133450 Neuroepithelioma 133450 Ewing sarcoma 133780 Vitreoretinopathy, exudative, familial 134820 Dysfibrinogenemia, alpha type, causing bleeding diathesis 134820 Dysfibrinogenemia, alpha type, causing recurrent thrombosis 134820 Amyloidosis, hereditary renal, 105200 134830 Dysfibrinogenemia, beta type 134850 Dysfibrinogenemia, gamma type 134850 Hypofibrinogenemia, gamma type 135700 Fibrosis of extraocular muscles, congenital, 1 136132 [Fish-odor syndrome], 602079 136836 Fucosyltransferase-6 deficiency 138079 Hyperinsulinism, familial, 602485 138079 MODY, type 2, 125851 138140 Glucose transport defect, blood-brain barrier 138190 Diabetes mellitus, noninsulin-dependent 138300 Hemolytic anemia due to glutathione reductase deficiency 138700 [Apolipoprotein H deficiency] 138720 Bernard-Soulier syndrome, type B 138981 Pulmonary alveolar proteinosis, 265120 139250 Isolated growth hormone deficiency, Illig type with absent GH and Kowarski type with bioinactive GH 139350 Epidermolytic hyperkeratosis, 113800 139350 Keratoderma, palmoplantar, nonepidermolytic 141750 Alpha-thalassemia/mental retardation syndrome, type 1 141800 Methemoglobinemias, alpha- 141800 Thalassemias, alpha- 141800 Erythremias, alpha- 141800 Heinz body anemias, alpha- 141850 Thalassemia, alpha- 141850 Erythrocytosis 141850 Heinz body anemia 141850 Hemoglobin H disease 141850 Hypochromic microcytic anemia 143890 Hypercholesterolemia, familial 145001 Hyperparathyroidism-jaw tumor syndrome 145260 Pseudohypoaldosteronism, type II 145410 Opitz G syndrome, type II 145981 Hypocalciuric hypercalcemia, type II 146150 Hypomelanosis of Ito 147050 Atopy 147141 Leukemia, acute lymphoblastic 147200 [Kappa light chain deficiency] 147670 Rabson-Mendenhall syndrome 147670 Diabetes mellitus, insulin-resistant, with acanthosis nigricans 147670 Leprechaunism 147781 Atopy, susceptibility to 148040 Epidermolysis bullosa simplex, Koebner, Dowling-Meara, and Weber- Cockayne types, 131900, 131760, 131800 148041 Pachyonychia congenita, Jadassohn-Lewandowsky type, 167200 148043 Meesmann corneal dystrophy, 122100 148070 Liver disease, susceptibility to, from hepatotoxins or viruses 148370 Keratolytic winter erythema 150200 [Placental lactogen deficiency] 150210 Lactoferrin-deficient neutrophils, 245480 150250 Larsen syndrome, autosomal dominant 150270 Laryngeal adductor paralysis 150292 Epidermolysis bullosa, Herlitz junctional type, 226700 151410 Leukemia, chronic myeloid 151440 Leukemia, T-cell acute lymphoblastoid 152760 Hypogonadotropic hypogonadism due to GNRH deficiency, 227200 153454 Ehlers-Danlos syndrome, type VI, 225400 153700 Macular dystrophy, vitelliform type 154275 Malignant hyperthermia susceptibility 2 154276 Malignant hyperthermia susceptibility 3 156850 Cataract, congenital, with microphthalmia 157147 Abetalipoproteinemia, 200100 157640 PEO with mitochondrial DNA deletions, type 1 160900 Myotonic dystrophy 161015 Mitochondrial complex I deficiency, 252010 162200 Neurofibromatosis, type 1 162200 Watson syndrome, 193520 164009 Leukemia, acute promyelocytic, NUMA/RARA type 164500 Spinocerebellar ataxia-7 164731 Ovarian carcinoma, 167000 164920 Piebaldism 164920 Mast cell leukemia 164920 Mastocytosis with associated hematologic disorder 164953 Liposarcoma 165240 Pallister-Hall syndrome, 146510 165240 Postaxial polydactyly type A1, 174200 165240 Greig cephalopolysyndactyly syndrome, 175700 165320 Hepatocellular carcinoma 166600 Osteopetrosis, AD, type II 168360 Paraneoplastic sensory neuropathy 168461 Multiple myeloma, 254250 168461 Parathyroid adenomatosis 1 168461 Centrocytic lymphoma 168468 Metaphyseal chondrodysplasia, Murk Jansen type, 156400 168470 Humoral hypercalcemia of malignancy 169600 Hailey-Hailey disease 170500 Myotonia congenita, atypical acetazolamide-responsive 170500 Paramyotonia congenita, 168300 170500 Hyperkalemic periodic paralysis 170650 Periodontitis, juvenile 170995 Zellweger syndrome-2 171760 Hypophosphatasia, adult, 146300 171760 Hypophosphatasia, infantile, 241500 172471 Glycogenosis, hepatic, autosomal 173360 Thrombophilia due to excessive plasminogen activator inhibitor 173360 Hemorrhagic diathesis due to PAI1 deficiency 173610 Platelet alpha/delta storage pool deficiency 173850 Polio, susceptibility to 173870 Xeroderma pigmentosum 173870 Fanconi anemia 174900 Polyposis, juvenile intestinal 176100 Porphyria cutanea tarda 176100 Porphyria, hepatoerythropoietic 176830 Obesity, adrenal insufficiency, and red hair 176830 ACTH deficiency 176960 Pituitary tumor, invasive 178300 Ptosis, hereditary congenital, 1 178640 Pulmonary alveolar proteinosis, congenital, 265120 180100 Retinitis pigmentosa-1 180104 Retinitis pigmentosa-9 180105 Retinitis pigmentosa-10 180297 Anemia, hemolytic, Rh-null, suppressor type, 268150 180380 Night blindness, congenital stationery, rhodopsin-related 180380 Retinitis pigmentosa, autosomal recessive 180380 Retinitis pigmentosa-4, autosomal dominant 180721 Retinitis pigmentosa, digenic 180840 Susceptibility to IDDM 181405 Scapuloperoneal spinal muscular atrophy, New England type 181430 Scapuloperoneal syndrome, myopathic type 181600 Sclerotylosis 182138 Anxiety-related personality traits 182279 Prader-Willi syndrome 182280 Small-cell cancer of lung 182381 Renal glucosuria, 253100 182600 Spastic paraplegia-3A 182601 Spastic paraplegia-4 182870 Spherocytosis-1 182870 Elliptocytosis-3 182870 Anemia, neonatal hemolytic, fatal and near-fatal 185430 Atherosclerosis, susceptibility to 186580 Arthrocutaneouveal granulomatosis 186921 Leukemia, T-cell acute lymphoblastic 187040 Leukemia-1, T-cell acute lymphoblastic 188070 Bleeding disorder due to defective thromboxane A2 receptor 188450 Goiter, adolescent multinodular 188450 Goiter, nonendemic, simple 188450 Hypothyroidism, hereditary congenital 188826 Sorsby fundus dystrophy, 136900 189800 Preeclampsia/eclampsia 190900 Colorblindness, tritan 191092 Tuberous sclerosis-2 191181 Cervical carcinoma 191540 [Urate oxidase deficiency] 192340 Diabetes insipidus, neurohypophyseal, 125700 193100 Hypophosphatemic rickets, autosomal dominant 193235 Vitreoretinopathy, neovascular inflammatory 193400 von Willebrand disease 200990 Acrocallosal syndrome 203200 Albinism, ocular, autosomal recessive 203200 Albinism, oculocutaneous, type II 203500 Alkaptonuria 203740 Alpha-ketoglutarate dehydrogenase deficiency 203800 Alstrom syndrome 207750 Hyperlipoproteinemia, type Ib 208250 Jacobs syndrome 209901 Bardet-Biedl syndrome 1 216900 Achromatopsia 219800 Cystinosis, nephropathic 222800 Hemolytic anemia due to bisphosphoglycerate mutase deficiency 224120 Dyserythropoietic anemia, contenital, type I 225500 Ellis-van Creveld syndrome 227220 [Eye color, brown] 227646 Fanconi anemia, type D 229800 [Fructosuria] 230000 Fucosidosis 231550 Achalasia-addisonianism-alacrimia syndrome 231670 Glutaricaciduria, type I 231950 Glutathioninuria 232050 Propionicacidemia, type II or pccB type 232300 Glycogen storage disease II 232400 Glycogen storage disease IIIa 232400 Glycogen storage disease IIIb 232600 McArdle disease 233700 Chronic granulomatous disease due to deficiency of NCF-1 234200 Neurodegeneration with brain iron accumulation 236730 Urofacial syndrome 238600 Chylomicronemia syndrome, familial 238600 Combined hyperlipemia, familial 238600 Hyperlipoproteinemia I 238600 Lipoprotein lipase deficiency 239100 Van Buchem disease 239500 Hyperprolinemia, type I 240400 Scurvy 245200 Krabbe disease 246900 Lipoamide dehydrogenase deficiency 247640 Leukemia, acute lymphoblastic 248510 Mannosidosis, beta- 248600 Maple syrup urine disease, type Ia 248611 Maple syrup urine disease, type Ib 249000 Meckel syndrome 249270 Thiamine-responsive megaloblastic anemia 251000 Methylmalonicaciduria, mutase deficiency type 251600 Microphthalmia, autosomal recessive 252900 Sanfilippo syndrome, type A 253250 Mulibrey nanism 254210 Myasthenia gravis, familial infantile 255800 Schwartz-Jampel syndrome 256700 Neuroblastoma 257220 Niemann-Pick disease, type C 257220 Niemann-Pick disease, type D, 257250 258501 3-methylglutaconicaciduria, type III 259700 Osteopetrosis, recessive 259770 Osteoporosis-pseudoglioma syndrome 261510 Pseudo-Zellweger syndrome 261670 Myopathy due to phosphoglycerate mutase deficiency 263200 Polycystic kidney disease, autosomal recessive 266150 Pyruvate carboxylase deficiency 266300 [Hair color, red] 266600 Inflammatory bowel disease-1 270100 Situs inversus viscerum 271900 Canavan disease 274270 Thymine-uraciluria 274270 Fluorouracil toxicity, sensitivity to 275350 Transcobalamin II deficiency 276900 Usher syndrome, type 1A 276902 Usher syndrome, type 3 276903 Usher syndrome, type 1B 276903 Deafness, autosomal dominant 11, neurosensory, 601317 276903 Deafness, autosomal recessive 2, neurosensory, 600060 277730 Wernicke-Korsakoff syndrome, susceptibility to 600045 Xeroderma pigmentosum, group E, subtype 2 600079 Colon cancer 600101 Deafness, autosomal dominant 2 600140 Rubenstein-Taybi syndrome, 180849 600143 Epilepsy, progressive, with mental retardation 600160 Melanoma, 155601 600163 Long QT syndrome-3 600179 Leber congenital amaurosis, type I, 204000 600194 Ichthyosis bullosa of Siemens, 146800 600211 Cleidocranial dysplasia, 119600 600221 Venous malformations, multiple cutaneous and mucosal, 600195 600231 Palmoplantar keratoderma, Bothnia type 600273 Polycystic kidney disease, infantile severe, with tuberous sclerosis 600276 Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, 125310 600309 Atrioventricular canal defect-1 600319 Diabetes mellitus, insulin-dependent, 4 600512 Epilepsy, partial 600528 CPT deficiency, hepatic, type I, 255120 600536 Myopathy, congenital 600593 Craniosynostosis, Adelaide type 600650 Myopathy due to CPT II deficiency, 255110 600650 CPT deficiency, hepatic, type II, 600649 600698 Salivary adenoma 600698 Uterine leiomyoma 600698 Lipoma 600698 Lipomatosis, mutiple, 151900 600701 Lipoma 600722 Ceroid lipofuscinosis, neuronal, variant juvenile type, with granular osmiophilic deposits 600722 Ceroid lipofuscinosis, neuronal-1, infantile, 256730 600759 Alzheimer disease-4 600760 Pseudohypoaldosteronism, type I, 264350 600760 Liddle syndrome, 177200 600761 Pseudohypoaldosteronism, type I, 264350 600761 Liddle syndrome, 177200 600808 Enuresis, nocturnal, 2 600839 Bartter syndrome, 241200 600850 Schizophrenia disorder-4 600881 Cataract, congenital, zonular, with sutural opacities 600882 Charcot-Marie-Tooth neuropathy-2B 600900 Muscular dystrophy, limb-girdle, type 2E 600956 Persistent Mullerian duct syndrome, type II, 261550 600957 Persistent Mullerian duct syndrome, type I, 261550 600971 Deafness, autosomal recessive 6 600977 Cone dystrophy, progressive 600983 Pseudohypoaldosteronism type I, autosomal dominant, 177735 600995 Nephrotic syndrome, idiopathic, steroid-resistant 600996 Arrhythmogenic right ventricular dysplasia-2 601154 Cardiomyopathy, dilated, 1E 601199 Neonatal hyperparathyroidism, 239200 601199 Hypocalcemia, autosomal dominant, 601198 601199 Hypocalciuric hypercalcemia, type I, 145980 601202 Cataract, anterior polar-2 601208 Insulin-dependent diabetes mellitus-11 601226 Progressive external ophthalmoplegia, type 2 601238 Cerebellar ataxia, Cayman type 601284 Hereditary hemorrhagic telangiectasia-2, 600376 601313 Polycystic kidney disease, adult type I, 173900 601385 Prostate cancer 601414 Retinitis pigmentosa-18 601458 Inflammatory bowel disease-2 601471 Moebius syndrome-2 601606 Trichoepithelioma, multiple familial 601623 Angelman syndrome 601649 Blepharophimosis, epicanthus inversus, and ptosis, type 2 601650 Paraganglioma, familial nonchromaffin, 2 601652 Glaucoma 1A, primary open angle, juvenile-onset, 137750 601669 Hirschsprung disease, one form 601682 Glaucoma 1C, primary open angle 601690 Platelet-activating factor acetylhydrolase deficiency 601691 Retinitis pigmentosa-19, 601718 601691 Stargardt disease-1, 248200 601691 Cone-rod dystrophy 3 601691 Fundus flavimaculatus with macular dystrophy, 248200 601718 Retinitis pigmentosa-19 601744 Systemic lupus erythematosus, susceptibility to, 1 601769 Osteoporosis, involutional 601769 Rickets, vitamin D-resistant, 277440 601777 Cone dystrophy, progessive 601785 Carbohydrate-deficient glycoprotein syndrome, type I, 212065 601800 [Hair color, brown] 601843 Hypothyroidism, congenital, 274400 601846 Muscular dystrophy with rimmed vacuoles 601884 [High bone mass] 601889 Lymphoma, diffuse large cell 601928 Monilethrix, 158000 601954 Muscular dystrophy, limb-girdle, type 2G 601975 Ectodermal dysplasia/skin fragility syndrome 602025 Obesity/hyperinsulinism, susceptibility to 602066 Convulsions, infantile and paroxysmal choreoathetosis 602092 Deafness, autosomal recessive 18 602094 Lipodystrophy, familial partial 602096 Alzheimer disease-5 602099 Amytrophic lateral sclerosis-5 602116 Glioma 602117 Prader-Willi syndrome 602134 Tremor, familial essential, 2 602136 Refsum disease, infantile, 266510 602136 Zellweger syndrome-1, 214100 602136 Adrenoleukodystrophy, neonatal, 202370 602153 Monilethrix, 158000 602216 Peutz-Jeghers syndrome, 175200 602363 Ellis-van Creveld-like syndrome 602403 Alzheimer disease, susceptibility to 602447 Coronary artery disease, susceptibility to 602477 Febrile convulsions, familial, 2 602568 Homocystinuria-megaloblastic anemia, cbl E type, 236270 602629 Dystonia-6, torsion Mature Polypeptides

The present invention also encompasses mature forms of a polypeptide having the amino acid sequence of SEQ ID NO:Y and/or the amino acid sequence encoded by the cDNA in a deposited clone. Polynucleotides encoding the mature forms (such as, for example, the polynucleotide sequence in SEQ ID NO:X and/or the polynucleotide sequence contained in the cDNA of a deposited clone) are also encompassed by the invention. Moreover, fragments or variants of these polypeptides (such as, fragments as described herein, polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to these polypeptides, or polypeptides encoded by a polynucleotide that hybridizes under stringent conditions to the complementary strand of the polynucleotide encoding these polypeptides) are also encompassed by the invention. In preferred embodiments, these fragments or variants retain one or more functional acitivities of the full-length or mature form of the polypeptide (e.g., biological activity (such as, for example, activity useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders), antigenicity (ability to bind, or compete with a polypeptide of the invention for binding, to an anti-polypeptide of the invention antibody), immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide of the invention). Antibodies that bind the polypeptides of the invention, and polynucleotides encoding these polypeptides are also encompassed by the invention.

According to the signal hypothesis, proteins secreted by mammalian cells have a signal or secretary leader sequence which is cleaved from the mature protein once export of the growing protein chain across the rough endoplasmic reticulum has been initiated. Most mammalian cells and even insect cells cleave secreted proteins with the same specificity. However, in some cases, cleavage of a secreted protein is not entirely uniform, which results in two or more mature species of the protein. Further, it has long been known that cleavage specificity of a secreted protein is ultimately determined by the primary structure of the complete protein, that is, it is inherent in the amino acid sequence of the polypeptide.

Methods for predicting whether a protein has a signal sequence, as well as the cleavage point for that sequence, are available. For instance, the method of McGeoch, Virus Res. 3:271-286 (1985), uses the information from a short N-terminal charged region and a subsequent uncharged region of the complete (uncleaved) protein. The method of von Heinje, Nucleic Acids Res. 14:4683-4690 (1986) uses the information from the residues surrounding the cleavage site, typically residues −13 to +2, where +1 indicates the amino terminus of the secreted protein. The accuracy of predicting the cleavage points of known mammalian secretory proteins for each of these methods is in the range of 75-80%. (von Heinje, supra.) However, the two methods do not always produce the same predicted cleavage point(s) for a given protein.

In the present case, the deduced amino acid sequence of the secreted polypeptide was analyzed by a computer program called SignalP (Henrik Nielsen et al., Protein Engineering 10:1-6 (1997)), which predicts the cellular location of a protein based on the amino acid sequence. As part of this computational prediction of localization, the methods of McGeoch and von Heinje are incorporated. The analysis of the amino acid sequences of the secreted proteins described herein by this program provided the results shown in Table 1A.

In specific embodiments, polypeptides of the invention comprise, or alternatively consist of, the predicted mature form of the polypeptide as delineated in columns 14 and 15 of Table 1A. Moreover, fragments or variants of these polypeptides (such as, fragments as described herein, polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to these polypeptides, or polypeptides encoded by a polynucleotide that hybridizes under stringent conditions to the complementary strand of the polynucleotide encoding these polypeptides) are also encompassed by the invention. In preferred embodiments, these fragments or variants retain one or more functional acitivities of the full-length or mature form of the polypeptide (e.g., biological activity (such as, for example, activity useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders), antigenicity (ability to bind, or compete with a polypeptide of the invention for binding, to an anti-polypeptide of the invention antibody), immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide of the invention). Antibodies that bind the polypeptides of the invention, and polynucleotides encoding these polypeptides are also encompassed by the invention.

Polynucleotides encoding proteins comprising, or consisting of, the predicted mature form of polypeptides of the invention (e.g., polynucleotides having the sequence of SEQ ID NO: X (Table 1A, column 4), the sequence delineated in columns 7 and 8 of Table 1A, and a sequence encoding the mature polypeptide delineated in columns 14 and 15 of Table 1A (e.g., the sequence of SEQ ID NO:X encoding the mature polypeptide delineated in columns 14 and 15 of Table 1)) are also encompassed by the invention, as are fragments or variants of these polynucleotides (such as, fragments as described herein, polynucleotides at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to these polyncueotides, and nucleic acids which hybridizes under stringent conditions to the complementary strand of the polynucleotide).

As one of ordinary skill would appreciate, however, cleavage sites sometimes vary from organism to organism and cannot be predicted with absolute certainty. Accordingly, the present invention provides secreted polypeptides having a sequence shown in SEQ ID NO:Y which have an N-terminus beginning within 15 residues of the predicted cleavage point (i.e., having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 more or less contiguous residues of SEQ ID NO:Y at the N-terminus when compared to the predicted mature form of the polypeptide (e.g., the mature polypeptide delineated in columns 14 and 15 of Table 1). Similarly, it is also recognized that in some cases, cleavage of the signal sequence from a secreted protein is not entirely uniform, resulting in more than one secreted species. These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.

Moreover, the signal sequence identified by the above analysis may not necessarily predict the naturally occurring signal sequence. For example, the naturally occurring signal sequence may be further upstream from the predicted signal sequence. However, it is likely that the predicted signal sequence will be capable of directing the secreted protein to the ER. Nonetheless, the present invention provides the mature protein produced by expression of the polynucleotide sequence of SEQ ID NO:X and/or the polynucleotide sequence contained in the cDNA of a deposited clone, in a mammalian cell (e.g., COS cells, as desribed below). These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.

Polynucleotide and Polypeptide Variants

The present invention is also directed to variants of the polynucleotide sequence disclosed in SEQ ID NO:X or the complementary strand thereto, nucleotide sequences encoding the polypeptide of SEQ ID NO:Y, the nucleotide sequence of SEQ ID NO:X that encodes the polypeptide sequence as defined in columns 13 and 14 of Table 1A, nucleotide sequences encoding the polypeptide sequence as defined in columns 13 and 14 of Table 1A, the nucleotide sequence of SEQ ID NO:X encoding the polypeptide sequence as defined in Table 1B, nucleotide sequences encoding the polypeptide as defined in Table 1B, the nucleotide sequence as defined in columns 8 and 9 of Table 2, nucleotide sequences encoding the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2, the nucleotide sequence as defined in column 6 of Table 1C, nucleotide sequences encoding the polypeptide encoded by the nucleotide sequence as defined in column 6 of Table 1C, the cDNA sequence contained in ATCC Deposit No:Z, nucleotide sequences encoding the polypeptide encoded by the cDNA sequence contained in ATCC Deposit No:Z, and/or nucleotide sequences encoding a mature (secreted) polypeptide encoded by the cDNA sequence contained in ATCC Deposit No:Z.

The present invention also encompasses variants of the polypeptide sequence disclosed in SEQ ID NO:Y, the polypeptide as defined in columns 13 and 14 of Table 1A, the polypeptide sequence as defined in Table 1B, a polypeptide sequence encoded by the polynucleotide sequence in SEQ ID NO:X, a polypeptide sequence encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2, a polypeptide sequence encoded by the nucleotide sequence as defined in column 6 of Table 1C, a polypeptide sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO:X, the polypeptide sequence encoded by the cDNA sequence contained in ATCC Deposit No:Z and/or a mature (secreted) polypeptide encoded by the cDNA sequence contained in ATCC Deposit No:Z.

“Variant” refers to a polynucleotide or polypeptide differing from the polynucleotide or polypeptide of the present invention, but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the polynucleotide or polypeptide of the present invention.

Thus, one aspect of the invention provides an isolated nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence described in SEQ ID NO:X or contained in the cDNA sequence of ATCC Deposit No:Z; (b) a nucleotide sequence in SEQ ID NO:X or the cDNA in ATCC Deposit No:Z which encodes the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; (c) a nucleotide sequence in SEQ ID NO:X or the cDNA in ATCC Deposit No:Z which encodes a mature polypeptide (i.e., a secreted polypeptide (e.g., as delineated in columns 14 and 15 of Table 1A)); (d) a nucleotide sequence in SEQ ID NO:X or the cDNA sequence of ATCC Deposit No:Z, which encodes a biologically active fragment of a polypeptide; (e) a nucleotide sequence in SEQ ID NO:X or the cDNA sequence of ATCC Deposit No:Z, which encodes an antigenic fragment of a polypeptide; (f) a nucleotide sequence encoding a polypeptide comprising the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; (g) a nucleotide sequence encoding a mature polypeptide of the amino acid sequence of SEQ ID NO:Y (i.e., a secreted polypeptide (e.g., as delineated in columns 14 and 15 of Table 1A)) or a mature polypeptide of the amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; (h) a nucleotide sequence encoding a biologically active fragment of a polypeptide having the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; (i) a nucleotide sequence encoding an antigenic fragment of a polypeptide having the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; and (j) a nucleotide sequence complementary to any of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g), (h), or (i) above.

The present invention is also directed to nucleic acid molecules which comprise, or alternatively consist of, a nucleotide sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example, any of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g), (h), (i), or (j) above, the nucleotide coding sequence in SEQ ID NO:X or the complementary strand thereto, the nucleotide coding sequence of the cDNA contained in ATCC Deposit No:Z or the complementary strand thereto, a nucleotide sequence encoding the polypeptide of SEQ ID NO:Y, a nucleotide sequence encoding a polypeptide sequence encoded by the nucleotide sequence in SEQ ID NO:X, a polypeptide sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO:X, a nucleotide sequence encoding the polypeptide encoded by the cDNA contained in ATCC Deposit No:Z, the nucleotide coding sequence in SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto, a nucleotide sequence encoding the polypeptide encoded by the nucleotide sequence in SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto, the nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1C or the complementary strand thereto, a nucleotide sequence encoding the polypeptide encoded by the nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1C or the complementary strand thereto, the nucleotide sequence in SEQ ID NO:X encoding the polypeptide sequence as defined in Table 1B or the complementary strand thereto, nucleotide sequences encoding the polypeptide as defined in Table 1B or the complementary strand thereto, and/or polynucleotide fragments of any of these nucleic acid molecules (e.g., those fragments described herein). Polynucleotides which hybridize to the complement of these nucleic acid molecules under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention, as are polypeptides encoded by these polynucleotides and nucleic acids.

In a preferred embodiment, the invention encompasses nucleic acid molecules which comprise, or alternatively, consist of a polynucleotide which hybridizes under stringent hybridization conditions, or alternatively, under lower stringency conditions, to a polynucleotide in (a), (b), (c), (d), (e), (f), (g), (h), or (i), above, as are polypeptides encoded by these polynucleotides. In another preferred embodiment, polynucleotides which hybridize to the complement of these nucleic acid molecules under stringent hybridization conditions, or alternatively, under lower stringency conditions, are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.

In another embodiment, the invention provides a purified protein comprising, or alternatively consisting of, a polypeptide having an arino acid sequence selected from the group consisting of: (a) the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; (b) the amino acid sequence of a mature (secreted) form of a polypeptide having the amino acid sequence of SEQ ID NO:Y (e.g., as delineated in columns 14 and 15 of Table 1A) or a mature form of the amino acid sequence encoded by the cDNA in ATCC Deposit No:Z nature; (c) the amino acid sequence of a biologically active fragment of a polypeptide having the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; and (d) the amino acid sequence of an antigenic fragment of a polypeptide having the complete amino acid sequence of SEQ ID NO:Y or the complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z.

The present invention is also directed to proteins which comprise, or alternatively consist of, an amino acid sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example, any of the amino acid sequences in (a), (b), (c), or (d), above, the amino acid sequence shown in SEQ ID NO:Y, the amino acid sequence encoded by the cDNA contained in ATCC Deposit No:Z, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO:X as defined in columns 8 and 9 of Table 2, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1C, the amino acid sequence as defined in Table 1B, an amino acid sequence encoded by the nucleotide sequence in SEQ ID NO:X, and an amino acid sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO:X. Fragments of these polypeptides are also provided (e.g., those fragments described herein). Further proteins encoded by polynucleotides which hybridize to the complement of the nucleic acid molecules encoding these amino acid sequences under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention, as are the polynucleotides encoding these proteins.

By a nucleic acid having a nucleotide sequence at least, for example, 95% “identical” to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the nucleic acid is identical to the reference sequence except that the nucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the polypeptide. In other words, to obtain a nucleic acid having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. The query sequence may be an entire sequence referred to in Table 1B or 2 as the ORF (open reading frame), or any fragment specified as described herein.

As a practical matter, whether any particular nucleic acid molecule or polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the present invention can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. 6:237-245 (1990)). In a sequence alignment the query and subject sequences are both DNA sequences. An RNA sequence can be compared by converting U's to T's. The result of said global sequence alignment is expressed as percent identity. Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identity are: Matrix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the length of the subject nucleotide sequence, whichever is shorter.

If the subject sequence is shorter than the query sequence because of 5′ or 3′ deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for 5′ and 3′ truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5′ or 3′ ends, relative to the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are 5′ and 3′ of the subject sequence, which are not matched/aligned, as a percent of the total bases of the query sequence. Whether a nucleotide is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present invention. Only bases outside the 5′ and 3′ bases of the subject sequence, as displayed by the FASTDB alignment, which are not matched/aligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score.

For example, a 90 base subject sequence is aligned to a 100 base query sequence to determine percent identity. The deletions occur at the 5′ end of the subject sequence and therefore, the FASTDB alignment does not show a matched/alignment of the first 10 bases at 5′ end. The 10 unpaired bases represent 10% of the sequence (number of bases at the 5′ and 3′ ends not matched/total number of bases in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 bases were perfectly matched the final percent identity would be 90%. In another example, a 90 base subject sequence is compared with a 100 base query sequence. This time the deletions are internal deletions so that there are no bases on the 5′ or 3′ of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only bases 5′ and 3′ of the subject sequence which are not matched/aligned with the query sequence are manually corrected for. No other manual corrections are to be made for the purposes of the present invention.

By a polypeptide having an amino acid sequence at least, for example, 95% “identical” to a query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a query amino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, (indels) or substituted with another amino acid. These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.

As a practical matter, whether any particular polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the amino acid sequence of a polypeptide referred to in Table 1A (e.g., the amino acid sequence delineated in columns 14 and 15) or a fragment thereof, Table 1B.1 (e.g., the amino acid sequence identified in column 6) or a fragment thereof, Table 2 (e.g., the amino acid sequence of the polypeptide encoded by the polynucleotide sequence defined in columns 8 and 9 of Table 2) or a fragment thereof, the amino acid sequence of the polypeptide encoded by the polynucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1C or a fragment thereof, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO:X or a fragment thereof, or the amino acid sequence of the polypeptide encoded by cDNA contained in ATCC Deposit No:Z, or a fragment thereof, the amino acid sequence of a mature (secreted) polypeptide encoded by cDNA contained in ATCC Deposit No:Z, or a fragment thereof, can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. 6:237-245 (1990)). In a sequence alignment the query and subject sequences are either both nucleotide sequences or both amino acid sequences. The result of said global sequence alignment is expressed as percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the subject amino acid sequence, whichever is shorter.

If the subject sequence is shorter than the query sequence due to N- or C-terminal deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for N- and C-terminal truncations of the subject sequence when calculating global percent identity. For subject sequences truncated at the N- and C-termini, relative to the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score. That is, only query residue positions outside the farthest N- and C-terminal residues of the subject sequence.

For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program If the remaining 90 residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a 100 residue query sequence. This time the deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.

The polynucleotide variants of the invention may contain alterations in the coding regions, non-coding regions, or both. Especially preferred are polynucleotide variants containing alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred. Moreover, polypeptide variants in which less than 50, less than 40, less than 30, less than 20, less than 10, or 5-50, 5-25, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination are also preferred. Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in the human mRNA to those preferred by a bacterial host such as E. coli).

Naturally occurring variants are called “allelic variants,” and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism (Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985)). These allelic variants can vary at either the polynucleotide and/or polypeptide level and are included in the present invention. Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.

Using known methods of protein engineering and recombinant DNA technology, variants may be generated to improve or alter the characteristics of the polypeptides of the present invention. For instance, one or more amino acids can be deleted from the N-terminus or C-terminus of the polypeptide of the present invention without substantial loss of biological function. As an example, Ron et al. (J. Biol. Chem. 268: 2984-2988 (1993)) reported variant KGF proteins having heparin binding activity even after deleting 3, 8, or 27 amino-terminal amino acid residues. Similarly, Interferon gamma exhibited up to ten times higher activity after deleting 8-10 amino acid residues from the carboxy terminus of this protein. (Dobeli et al., J. Biotechnology 7:199-216 (1988).)

Moreover, ample evidence demonstrates that variants often retain a biological activity similar to that of the naturally occurring protein. For example, Gayle and coworkers (J. Biol. Chem. 268:22105-22111 (1993)) conducted extensive mutational analysis of human cytokine IL-1a. They used random mutagenesis to generate over 3,500 individual IL-1a mutants that averaged 2.5 amino acid changes per variant over the entire length of the molecule. Multiple mutations were examined at every possible amino acid position. The investigators found that “[m]ost of the molecule could be altered with little effect on either [binding or biological activity].” In fact, only 23 unique amino acid sequences, out of more than 3,500 nucleotide sequences examined, produced a protein that significantly differed in activity from wild-type.

Furthermore, even if deleting one or more amino acids from the N-terminus or C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus. Whether a particular polypeptide lacking N- or C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.

Thus, the invention further includes polypeptide variants which show a biological or functional activity of the polypeptides of the invention (such as, for example, activity useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders). Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity.

The present application is directed to nucleic acid molecules at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleic acid sequences disclosed herein, (e.g., encoding a polypeptide having the amino acid sequence of an N and/or C terminal deletion), irrespective of whether they encode a polypeptide having functional activity. This is because even where a particular nucleic acid molecule does not encode a polypeptide having functional activity, one of skill in the art would still know how to use the nucleic acid molecule, for instance, as a hybridization probe or a polymerase chain reaction (PCR) primer. Uses of the nucleic acid molecules of the present invention that do not encode a polypeptide having functional activity include, inter alia, (1) isolating a gene or allelic or splice variants thereof in a cDNA library; (2) in situ hybridization (e.g., “FISH”) to metaphase chromosomal spreads to provide precise chromosomal location of the gene, as described in Verma et al., Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York (1988); (3) Northern Blot analysis for detecting mRNA expression in specific tissues (e.g., normal or diseased tissues); and (4) in situ hybridization (e.g., histochemistry) for detecting mRNA expression in specific tissues (e.g., normal or diseased tissues).

Preferred, however, are nucleic acid molecules having sequences at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleic acid sequences disclosed herein, which do, in fact, encode a polypeptide having functional activity. By a polypeptide having “functional activity” is meant, a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) protein and/or a mature (secreted) protein of the invention. Such functional activities include, but are not limited to, biological activity (such as, for example, activity useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders), antigenicity (ability to bind, or compete with a polypeptide of the invention for binding, to an anti-polypeptide of the invention antibody), immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide of the invention.

The functional activity of the polypeptides, and fragments, variants and derivatives of the invention, can be assayed by various methods.

For example, in one embodiment where one is assaying for the ability to bind or compete with a full-length polypeptide of the present invention for binding to an anti-polypetide antibody, various immunoassays known in the art can be used, including but not limited to, competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), western blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc. In one embodiment, antibody binding is detected by detecting a label on the primary antibody. In another embodiment, the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention.

In another embodiment, where a ligand is identified, or the ability of a polypeptide fragment, variant or derivative of the invention to multimerize is being evaluated, binding can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky et al., Microbiol. Rev. 59:94-123 (1995). In another embodiment, the ability of physiological correlates of a polypeptide of the present invention to bind to a substrate(s) of the polypeptide of the invention can be routinely assayed using techniques known in the art.

In addition, assays described herein (see Examples) and otherwise known in the art may routinely be applied to measure the ability of polypeptides of the present invention and fragments, variants and derivatives thereof to elicit polypeptide related biological activity (either in vitro or in vivo). Other methods will be known to the skilled artisan and are within the scope of the invention.

Of course, due to the degeneracy of the genetic code, one of ordinary skill in the art will immediately recognize that a large number of the nucleic acid molecules having a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to, for example, the nucleic acid sequence of the cDNA contained in ATCC Deposit No:Z, the nucleic acid sequence referred to in Table 1B (SEQ ID NO:X), the nucleic acid sequence disclosed in Table 1A (e.g., the nucleic acid sequence delineated in columns 7 and 8), the nucleic acid sequence disclosed in Table 2 (e.g., the nucleic acid sequence delineated in columns 8 and 9) or fragments thereof, will encode polypeptides “having functional activity.” In fact, since degenerate variants of any of these nucleotide sequences all encode the same polypeptide, in many instances, this will be clear to the skilled artisan even without performing the above described comparison assay. It will be further recognized in the art that, for such nucleic acid molecules that are not degenerate variants, a reasonable number will also encode a polypeptide having functional activity. This is because the skilled artisan is fully aware of amino acid substitutions that are either less likely or not likely to significantly effect protein function (e.g., replacing one aliphatic amino acid with a second aliphatic amino acid), as further described below.

For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie et al., “Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990), wherein the authors indicate that there are two main strategies for studying the tolerance of an amino acid sequence to change.

The first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.

The second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function. For example, site directed mutagenesis or alanine-scanning mutagenesis (introduction of single alanine mutations at every residue in the molecule) can be used. See Cunningham and Wells, Science 244:1081-1085 (1989). The resulting mutant molecules can then be tested for biological activity.

As the authors state, these two strategies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at certain amino acid positions in the protein. For example, most buried (within the tertiary structure of the protein) amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Moreover, tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.

Besides conservative amino acid substitution, variants of the present invention include (i) substitutions with one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) substitutions with one or more of the amino acid residues having a substituent group, or (iii) fusion of the mature polypeptide with another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), (iv) fusion of the polypeptide with additional amino acids, such as, for example, an IgG Pc fusion region peptide, serum albumin (preferably human serum albumin) or a fragment thereof, or leader or secretory sequence, or a sequence facilitating purification, or (v) fusion of the polypeptide with another compound, such as albumin (including but not limited to recombinant albumin (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)). Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.

For example, polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate's immunogenic activity. See Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967); Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev. Therapeutic Drug Carrier Systems 10:307-377 (1993).

A further embodiment of the invention relates to polypeptides which comprise the amino acid sequence of a polypeptide having an amino acid sequence which contains at least one amino acid substitution, but not more than 50 amino acid substitutions, even more preferably, not more than 40 amino acid substitutions, still more preferably, not more than 30 amino acid substitutions, and still even more preferably, not more than 20 amino acid substitutions from a polypeptide sequence disclosed herein. Of course it is highly preferable for a polypeptide to have an amino acid sequence which, for example, comprises the amino acid sequence of a polypeptide of SEQ ID NO:Y, the amino acid sequence of the mature (e.g., secreted) polypeptide of SEQ ID NO:Y, an amino acid sequence encoded by SEQ ID NO:X, an amino acid sequence encoded by the portion of SEQ ID NO:X as defined in columnns 8 and 9 of Table 2, an amino acid sequence encoded by the complement of SEQ ID NO:X, an amino acid sequence encoded by cDNA contained in ATCC Deposit No:Z, and/or the amino acid sequence of a mature (secreted) polypeptide encoded by cDNA contained in ATCC Deposit No:Z, or a fragment thereof, which contains, in order of ever-increasing preference, at least one, but not more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions.

In specific embodiments, the polypeptides of the invention comprise, or alternatively, consist of, fragments or variants of a reference amino acid sequence selected from: (a) the amino acid sequence of SEQ ID NO:Y or fragments thereof (e.g., the mature form and/or other fragments described herein); (b) the amino acid sequence encoded by SEQ ID NO:X or fragments thereof; (c) the amino acid sequence encoded by the complement of SEQ ID NO:X or fragments thereof; (d) the amino acid sequence encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or fragments thereof; and (e) the amino acid sequence encoded by cDNA contained in ATCC Deposit No:Z or fragments thereof; wherein the fragments or variants have 1-5, 5-25, 5-50, 10-50 or 50-150, amino acid residue additions, substitutions, and/or deletions when compared to the reference amino acid sequence. In preferred embodiments, the amino acid substitutions are conservative. Polynucleotides encoding these polypeptides are also encompassed by the invention.

Polynucleotide and Polypeptide Fragments

The present invention is also directed to polynucleotide fragments of the polynucleotides (nucleic acids) of the invention. In the present invention, a “polynucleotide fragment” refers to a polynucleotide having a nucleic acid sequence which, for example: is a portion of the cDNA contained in ATCC Deposit No:Z or the complementary strand thereto; is a portion of the polynucleotide sequence encoding the polypeptide encoded by the cDNA contained in ATCC Deposit No:Z or the complementary strand thereto; is a portion of the polynucleotide sequence encoding the mature (secreted) polypeptide encoded by the cDNA contained in ATCC Deposit No:Z or the complementary strand thereto; is a portion of a polynucleotide sequence encoding the mature amino acid sequence as defined in columns 14 and 15 of Table 1A or the complementary strand thereto; is a portion of a polynucleotide sequence encoding the amino acid sequence encoded by the region of SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto; is a portion of the polynucleotide sequence of SEQ ID NO:X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto; is a portion of the polynucleotide sequence in SEQ ID NO:X or the complementary strand thereto; is a polynucleotide sequence encoding a portion of the polypeptide of SEQ ID NO:Y; is a polynucleotide sequence encoding a portion of a polypeptide encoded by SEQ ID NO:X; is a polynucleotide sequence encoding a portion of a polypeptide encoded by the complement of the polynucleotide sequence in SEQ ID NO:X; is a portion of a polynucleotide sequence encoding the amino acid sequence encoded by the region of SEQ ID NO:B as defined in column 6 of Table 1C or the complementary strand thereto; or is a portion of the polynucleotide sequence of SEQ ID NO:B as defined in column 6 of Table 1C or the complementary strand thereto.

The polynucleotide fragments of the invention are preferably at least about 15 nt, and more preferably at least about 20 nt, still more preferably at least about 30 nt, and even more preferably, at least about 40 nt, at least about 50 nt, at least about 75 nt, or at least about 150 nt in length. A fragment “at least 20 nt in length,” for example, is intended to include 20 or more contiguous bases from the cDNA sequence contained in ATCC Deposit No:Z, or the nucleotide sequence shown in SEQ ID NO:X or the complementary stand thereto. In this context “about” includes the particularly recited value or a value larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. These nucleotide fragments have uses that include, but are not limited to, as diagnostic probes and primers as discussed herein. Of course, larger fragments (e.g., at least 160, 170, 180, 190, 200, 250, 500, 600, 1000, or 2000 nucleotides in length) are also encompassed by the invention.

Moreover, representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a sequence from about nucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 601-650, 651-700, 701-750, 751-800, 801-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250, 2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550, 2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850, 2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150, 3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450, 3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750, 3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050, 4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350, 4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650, 4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950, 4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250, 5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550, 5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850, 5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150, 6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450, 6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750, 6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050, 7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the end of SEQ ID NO:X, or the complementary strand thereto. In this context “about” includes the particularly recited range or a range larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. Preferably, these fragments encode a polypeptide which has a functional activity (e.g., biological activity; such as, for example, activity useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders). More preferably, these polynucleotides can be used as probes or primers as discussed herein. Polynucleotides which hybridize to one or more of these polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.

Further representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a sequence from about nucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 601-650, 651-700, 701-750, 751-800, 801-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250, 2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550, 2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850, 2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150, 3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450, 3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750, 3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050, 4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350, 4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650, 4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950, 4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250, 5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550, 5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850, 5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150, 6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450, 6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750, 6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050, 7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the end of the cDNA sequence contained in ATCC Deposit No:Z, or the complementary strand thereto. In this context “about” includes the particularly recited range or a range larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. Preferably, these fragments encode a polypeptide which has a functional activity (e.g., biological activity). More preferably, these polynucleotides can be used as probes or primers as discussed herein. Polynucleotides which hybridize to one or more of these polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.

Moreover, representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a nucleic acid sequence comprising one, two, three, four, five, six, seven, eight, nine, ten, or more of the above described polynucleotide fragments of the invention in combination with a polynucleotide sequence delineated in Table 1C column 6. Additional, representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a nucleic acid sequence comprising one, two, three, four, five, six, seven, eight, nine, ten, or more of the above described polynucleotide fragments of the invention in combination with a polynucleotide sequence that is the complementary strand of a sequence delineated in column 6 of Table 1C. In further embodiments, the above-described polynucleotide fragments of the invention comprise, or alternatively consist of, sequences delineated in Table 1C, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1C, column 5). In additional embodiments, the above-described polynucleotide fragments of the invention comprise, or alternatively consist of, sequences delineated in Table 1C, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated Table 1C, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in column 6 of Table 1C, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1C, column 2) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in column 6 of Table 1C which correspond to the same ATCC Deposit No:Z (see Table 1C, column 1), and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A, 1B, or 1C) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in the same row of column 6 of Table 1C, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A, 1B, or 1C) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C and the 5′ 10 polynucleotides of the sequence of SEQ ID NO:X are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C and the 5′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X (e.g., as described herein) are directly contiguous Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1C are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C and the 5′ 10 polynucleotides of another sequence in column 6 are directly contiguous. In preferred embodiments, the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1C is directly contiguous with the 5′ 10 polynucleotides of the next sequential exon delineated in Table 1C, column 6. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

In the present invention, a “polypeptide fragment” refers to an amino acid sequence which is a portion of the amino acid sequence contained in SEQ ID NO:Y, is a portion of the mature form of SEQ ID NO:Y as defined in columns 14 and 15 of Table 1A, a portion of an amino acid sequence encoded by the portion of SEQ ID NO:X as defined in columnns 8 and 9 of Table 2, is a portion of an amino acid sequence encoded by the polynucleotide sequence of SEQ ID NO:X, is a portion of an amino acid sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO:X, is a portion of the amino acid sequence of a mature (secreted) polypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/or is a portion of an amino acid sequence encoded by the cDNA contained in ATCC Deposit No:Z. Protein (polypeptide) fragments may be “free-standing,” or comprised within a larger polypeptide of which the fragment forms a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments comprising, or alternatively consisting of, from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, 101-120, 121-140, 141-160, 161-180, 181-200, 201-220, 221-240, 241-260, 261-280, 281-300, 301-320, 321-340, 341-360, 361-380, 381-400, 401-420, 421-440, 441-460, 461-480, 481-500, 501-520, 521-540, 541-560, 561-580, 581-600, 601-620, 621-640, 641-660, 661-680, 681-700, 701-720, 721-740, 741-760, 761-780, 781-800, 801-820, 821-840, 841-860, 861-880, 881-900, 901-920, 921-940, 941-960, 961-980, 981-1000, 1001-1020, 1021-1040, 1041-1060, 1061-1080, 1081-1100, 1101-1120, 1121-1140, 1141-1160, 1161-1180, 1181-1200, 1201-1220, 1221-1240, 1241-1260, 1261-1280, 1281-1300, 1301-1320, 1321-1340, 1341-1360, 1361-1380, 1381-1400, 1401-1420, 1421-1440, or 1441 to the end of the coding region of cDNA and SEQ ID NO: Y. In a preferred embodiment, polypeptide fragments of the invention include, for example, fragments comprising, or alternatively consisting of, from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, 101-120, 121-140, 141-160, 161-180, 181-200, 201-220, 221-240, 241-260, 261-280, 281-300, 301-320, 321-340, 341-360, 361-380, 381-400, 401-420, 421-440, 441-460, 461-480, 481-500, 501-520, 521-540, 541-560, 561-580, 581-600, 601-620, 621-640, 641-660, 661-680, 681-700, 701-720, 721-740, 741-760, 761-780, 781-800, 801-820, 821-840, 841-860, 861-880, 881-900, 901-920, 921-940, 941-960, 961-980, 981-1000, 1001-1020, 1021-1040, 1041-1060, 1061-1080, 1081-1100, 1101-1120, 1121-1140, 1141-1160, 1161-1180, 1181-1200, 1201-1220, 1221-1240, 1241-1260, 1261-1280, 1281-1300, 1301-1320, 1321-1340, 1341-1360, 1361-1380, 1381-1400, 1401-1420, 1421-1440, or 1441 to the end of the coding region of SEQ ID NO:Y. Moreover, polypeptide fragments of the invention may be at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, or 150 amino acids in length. In this context “about” includes the particularly recited ranges or values, or ranges or values larger or smaller by several (5, 4, 3, 2, or 1) amino acids, at either extreme or at both extremes. Polynucleotides encoding these polypeptide fragments are also encompassed by the invention.

Even if deletion of one or more amino acids from the N-terminus of a protein results in modification of loss of one or more biological functions of the protein, other functional activities (e.g., biological activities; such as, for example, activity useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders; ability to multimerize; ability to bind a ligand; antigenic ability useful for production of polypeptide specific antibodies) may still be retained. For example, the ability of shortened muteins to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptides generally will be retained when less than the majority of the residues of the complete or mature polypeptide are removed from the N-terminus. Whether a particular polypeptide lacking N-terminal residues of a complete polypeptide retains such immunologic activities can readily be determined by routine methods described herein and otherwise known in the art. It is not unlikely that a mutein with a large number of deleted N-terminal amino acid residues may retain some biological or immunogenic activities. In fact, peptides composed of as few as six amino acid residues may often evoke an immune response.

Accordingly, polypeptide fragments include the secreted protein as well as the mature form. Further preferred polypeptide fragments include the secreted protein or the mature form having a continuous series of deleted residues from the amino or the carboxy terminus, or both. For example, any number of amino acids, ranging from 1-60, can be deleted from the amino terminus of either the secreted polypeptide or the mature form. Similarly, any number of amino acids, ranging from 1-30, can be deleted from the carboxy terminus of the secreted protein or mature form. Furthermore, any combination of the above amino and carboxy terminus deletions are preferred. Similarly, polynucleotides encoding these polypeptide fragments are also preferred.

The present invention further provides polypeptides having one or more residues deleted from the amino terminus of the amino acid sequence of a polypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO:Y, a polypeptide as defined in columns 14 and 15 of Table 1A, a polypeptide encoded by the polynucleotide sequence contained in SEQ ID NO:X or the complement thereof, a polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, a polypeptide encoded by the portion of SEQ ID NO:B as defined in column 6 of Table 1C, a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/or a mature polypeptide encoded by the cDNA contained in ATCC Deposit No:Z). In particular, N-terminal deletions may be described by the general formula m-q, where q is a whole integer representing the total number of amino acid residues in a polypeptide of the invention (e.g., the polypeptide disclosed in SEQ ID NO:Y, the mature (secreted) portion of SEQ ID NO:Y as defined in columns 14 and 15 of Table 1A, or the polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2), and m is defined as any integer ranging from 2 to q-6. Polynucleotides encoding these polypeptides are also encompassed by the invention.

The present invention further provides polypeptides having one or more residues from the carboxy terminus of the amino acid sequence of a polypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO:Y, the mature (secreted) portion of SEQ ID NO:Y as defined in columns 14 and 15 of Table 1A, a polypeptide encoded by the polynucleotide sequence contained in SEQ ID NO:X, a polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, a polypeptide encoded by the portion of SEQ ID NO:B as defined in column 6 of Table 1C, a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/or a mature polypeptide encoded by the cDNA contained in ATCC Deposit No:Z). In particular, C-terminal deletions may be described by the general formula 1-n, where n is any whole integer ranging from 6 to q-1, and where n corresponds to the position of amino acid residue in a polypeptide of the invention. Polynucleotides encoding these polypeptides are also encompassed by the invention.

In addition, any of the above described N- or C-terminal deletions can be combined to produce a N- and C-terminal deleted polypeptide. The invention also provides polypeptides having one or more amino acids deleted from both the amino and the carboxyl termini, which may be described generally as having residues m-n of a polypeptide encoded by SEQ ID NO:X (e.g., including, but not limited to, the preferred polypeptide disclosed as SEQ ID NO:Y, the mature (secreted) portion of SEQ ID NO:Y as defined in columns 14 and 15 of Table 1A, and the polypeptide encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2), the cDNA contained in ATCC Deposit No:Z, and/or the complement thereof, where n and m are integers as described above. Polynucleotides encoding these polypeptides are also encompassed by the invention.

Also as mentioned above, even if deletion of one or more amino acids from the C-terminus of a protein results in modification of loss of one or more biological functions of the protein, other functional activities (e.g., biological activities such as, for example, activity useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders; ability to multimerize; ability to bind a ligand; antigenic ability useful for production of polypeptide specific antibodies) may still be retained. For example the ability of the shortened mutein to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptide generally will be retained when less than the majority of the residues of the complete or mature polypeptide are removed from the C-terminus. Whether a particular polypeptide lacking C-terminal residues of a complete polypeptide retains such immunologic activities can readily be determined by routine methods described herein and otherwise known in the art. It is not unlikely that a mutein with a large number of deleted C-terminal amino acid residues may retain some biological or immunogenic activities. In fact, peptides composed of as few as six amino acid residues may often evoke an immune response.

The present application is also directed to proteins containing polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a polypeptide sequence set forth herein. In preferred embodiments, the application is directed to proteins containing polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to polypeptides having the amino acid sequence of the specific N- and C-terminal deletions. Polynucleotides encoding these polypeptides are also encompassed by the invention.

Any polypeptide sequence encoded by, for example, the polynucleotide sequences set forth as SEQ ID NO:X or the complement thereof, (presented, for example, in Tables 1A and 2), the cDNA contained in ATCC Deposit No:Z, or the polynucleotide sequence as defined in column 6 of Table 1C, may be analyzed to determine certain preferred regions of the polypeptide. For example, the amino acid sequence of a polypeptide encoded by a polynucleotide sequence of SEQ ID NO:X (e.g., the polypeptide of SEQ ID NO:Y and the polypeptide encoded by the portion of SEQ ID NO:X as defined in columnns 8 and 9 of Table 2) or the cDNA contained in ATCC Deposit No:Z may be analyzed using the default parameters of the DNASTAR computer algorithm (DNASTAR, Inc., 1228 S. Park St., Madison, Wis. 53715 USA; http://www.dnastar.com/).

Polypeptide regions that may be routinely obtained using the DNASTAR computer algorithm include, but are not limited to, Garnier-Robson alpha-regions, beta-regions, turn-regions, and coil-regions; Chou-Fasman alpha-regions, beta-regions, and turn-regions; Kyte-Doolittle hydrophilic regions and hydrophobic regions; Eisenberg alpha- and beta-amphipathic regions; Karplus-Schulz flexible regions; Emini surface-forming regions; and Jameson-Wolf regions of high antigenic index. Among highly preferred polynucleotides of the invention in this regard are those that encode polypeptides comprising regions that combine several structural features, such as several (e.g., 1, 2, 3 or 4) of the features set out above.

Additionally, Kyte-Doolittle hydrophilic regions and hydrophobic regions, Emini surface-forming regions, and Jameson-Wolf regions of high antigenic index (i.e., containing four or more contiguous amino acids having an antigenic index of greater than or equal to 1.5, as identified using the default parameters of the Jameson-Wolf program) can routinely be used to determine polypeptide regions that exhibit a high degree of potential for antigenicity. Regions of high antigenicity are determined from data by DNASTAR analysis by choosing values which represent regions of the polypeptide which are likely to be exposed on the surface of the polypeptide in an environment in which antigen recognition may occur in the process of initiation of an immune response.

Preferred polypeptide fragments of the invention are fragments comprising, or alternatively, consisting of, an amino acid sequence that displays a functional activity (e.g. biological activity such as, for example, activity useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and hematologic diseases and disorders; ability to multimerize; ability to bind a ligand; antigenic ability useful for production of polypeptide specific antibodies) of the polypeptide sequence of which the amino acid sequence is a fragment. By a polypeptide displaying a “functional activity” is meant a polypeptide capable of one or more known functional activities associated with a full-length protein, such as, for example, biological activity, antigenicity, immunogenicity, and/or multimerization, as described herein.

Other preferred polypeptide fragments are biologically active fragments. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.

In preferred embodiments, polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the antigenic fragments of the polypeptide of SEQ ID NO:Y, or portions thereof. Polynucleotides encoding these polypeptides are also encompassed by the invention.

Epitopes and Antibodies

The present invention encompasses polypeptides comprising, or alternatively consisting of, an epitope of: the polypeptide sequence shown in SEQ ID NO:Y; a polypeptide sequence encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide sequence encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2; the polypeptide sequence encoded by the portion of SEQ ID NO:B as defined in column 6 of Table 1C or the complement thereto; the polypeptide sequence encoded by the cDNA contained in ATCC Deposit No:Z; or the polypeptide sequence encoded by a polynucleotide that hybridizes to the sequence of SEQ ID NO:X, the complement of the sequence of SEQ ID NO:X, the complement of a portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, or the cDNA sequence contained in ATCC Deposit No:Z under stringent hybridization conditions or alternatively, under lower stringency hybridization as defined supra. The present invention further encompasses polynucleotide sequences encoding an epitope of a polypeptide sequence of the invention (such as, for example, the sequence disclosed in SEQ ID NO:X, or a fragment thereof), polynucleotide sequences of the complementary strand of a polynucleotide sequence encoding an epitope of the invention, and polynucleotide sequences which hybridize to the complementary strand under stringent hybridization conditions or alternatively, under lower stringency hybridization conditions defined supra.

The term “epitopes,” as used herein, refers to portions of a polypeptide having antigenic or immunogenic activity in an animal, preferably a mammal, and most preferably in a human. In a preferred embodiment, the present invention encompasses a polypeptide comprising an epitope, as well as the polynucleotide encoding this polypeptide. An “immunogenic epitope,” as used herein, is defined as a portion of a protein that elicits an antibody response in an animal, as determined by any method known in the art, for example, by the methods for generating antibodies described infra. (See, for example, Geysen et al., Proc. Natl. Acad. Sci. USA 81:3998-4002 (1983)). The term “antigenic epitope,” as used herein, is defined as a portion of a protein to which an antibody can immunospecifically bind its antigen as determined by any method well known in the art, for example, by the immunoassays described herein. Immunospecific binding excludes non-specific binding but does not necessarily exclude cross-reactivity with other antigens. Antigenic epitopes need not necessarily be immunogenic.

Fragments which function as epitopes may be produced by any conventional means. (See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985) further described in U.S. Pat. No. 4,631,211.)

In the present invention, antigenic epitopes preferably contain a sequence of at least 4, at least 5, at least 6, at least 7, more preferably at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, and, most preferably, between about 15 to about 30 amino acids. Preferred polypeptides comprising immunogenic or antigenic epitopes are at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acid residues in length. Additional non-exclusive preferred antigenic epitopes include the antigenic epitopes disclosed herein, as well as portions thereof. Antigenic epitopes are useful, for example, to raise antibodies, including monoclonal antibodies, that specifically bind the epitope. Preferred antigenic epitopes include the antigenic epitopes disclosed herein, as well as any combination of two, three, four, five or more of these antigenic epitopes. Antigenic epitopes can be used as the target molecules in immunoassays. (See, for instance, Wilson et al., Cell 37:767-778 (1984); Sutcliffe et al., Science 219:660-666 (1983)).

Non-limiting examples of epitopes of polypeptides that can be used to generate antibodies of the invention include a polypeptide comprising, or alternatively consisting of, at least one, two, three, four, five, six or more of the portion(s) of SEQ ID NO:Y specified in Table 1B. These polypeptide fragments have been determined to bear antigenic epitopes of the proteins of the invention by the analysis of the Jameson-Wolf antigenic index which is included in the DNAStar suite of computer programs. By “comprise” it is intended that a polypeptide contains at least one, two, three, four, five, six or more of the portion(s) of SEQ ID NO:Y shown in Table 1B, but it may contain additional flanking residues on either the amino or carboxyl termini of the recited portion. Such additional flanking sequences are preferably sequences naturally found adjacent to the portion; i.e., contiguous sequence shown in SEQ ID NO:Y. The flanking sequence may, however, be sequences from a heterolgous polypeptide, such as from another protein described herein or from a heterologous polypeptide not described herein. In particular embodiments, epitope portions of a polypeptide of the invention comprise one, two, three, or more of the portions of SEQ ID NO:Y shown in Table 1B.

Similarly, immunogenic epitopes can be used, for example, to induce antibodies according to methods well known in the art. See, for instance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle et al., J. Gen. Virol. 66:2347-2354 (1985). Preferred immunogenic epitopes include the immunogenic epitopes disclosed herein, as well as any combination of two, three, four, five or more of these-immunogenic epitopes. The polypeptides comprising one or more immunogenic epitopes may be presented for eliciting an antibody response together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse), or, if the polypeptide is of sufficient length (at least about 25 amino acids), the polypeptide may be presented without a carrier. However, immunogenic epitopes comprising as few as 8 to 10 amino acids have been shown to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a denatured polypeptide (e.g., in Western blotting).

Epitope-bearing polypeptides of the present invention may be used to induce antibodies according to methods well known in the art including, but not limited to, in vivo immunization, in vitro immunization, and phage display methods. See, e.g., Sutcliffe et al., supra; Wilson et al., supra, and Bittle et al., J. Gen. Virol., 66:2347-2354 (1985). If in vivo immunization is used, animals may be immunized with free peptide; however, anti-peptide antibody titer may be boosted by coupling the peptide to a macromolecular carrier, such as keyhole limpet hemacyanin (KLH) or tetanus toxoid. For instance, peptides containing cysteine residues may be coupled to a carrier using a linker such as maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptides may be coupled to carriers using a more general linking agent such as glutaraldehyde. Animals such as rabbits, rats and mice are immunized with either free or carrier-coupled peptides, for instance, by intraperitoneal and/or intradermal injection of emulsions containing about 100 μg of peptide or carrier protein and Freund's adjuvant or any other adjuvant known for stimulating an immune response. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptide antibody which can be detected, for example, by ELISA assay using free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in serum from an immunized animal may be increased by selection of anti-peptide antibodies, for instance, by adsorption to the peptide on a solid support and elution of the selected antibodies according to methods well known in the art.

As one of skill in the art will appreciate, and as discussed above, the polypeptides of the present invention (e.g., those comprising an immunogenic or antigenic epitope) can be fused to heterologous polypeptide sequences. For example, polypeptides of the present invention (including fragments or variants thereof), may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof and portions thereof, resulting in chimeric polypeptides. By way of another non-limiting example, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) may be fused with albumin (including but not limited to recombinant human serum albumin or fragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)). In a preferred embodiment, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) are fused with the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin as shown in FIGS. 1 and 2 of EP Patent 0 322 094) which is herein incorporated by reference in its entirety. In another preferred embodiment, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) are fused with polypeptide fragments comprising, or alternatively consisting of, amino acid residues 1-z of human serum albumin, where z is an integer from 369 to 419, as described in U.S. Pat. No. 5,766,883 herein incorporated by reference in its entirety. Polypeptides and/or antibodies of the present invention (including fragments or variants thereof) may be fused to either the N- or C-terminal end of the heterologous protein (e.g., immunoglobulin Fc polypeptide or human serum albumin polypeptide). Polynucleotides encoding fusion proteins of the invention are also encompassed by the invention.

Such fusion proteins as those described above may facilitate purification and may increase half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, e.g., EP 394,827; Traunecker et al., Nature, 331:84-86 (1988). Enhanced delivery of an antigen across the epithelial barrier to the immune system has been demonstrated for antigens (e.g., insulin) conjugated to an FcRn binding partner such as IgG or Fc fragments (see, e.g., PCT Publications WO 96/22024 and WO 99/04813). IgG fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion desulfide bonds have also been found to be more efficient in binding and neutralizing other molecules than monomeric polypeptides or fragments thereof alone. See, e.g., Fountoulakis et al., J. Biochem., 270:3958-3964 (1995). Nucleic acids encoding the above epitopes can also be recombined with a gene of interest as an epitope tag (e.g., the hemagglutinin (HA) tag or flag tag) to aid in detection and purification of the expressed polypeptide. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-897). In this system, the gene of interest is subcloned into a vaccinia recombination plasmid such that the open reading frame of the gene is translationally fused to an amino-terminal tag consisting of six histidine residues. The tag serves as a matrix binding domain for the fusion protein. Extracts from cells infected with the recombinant vaccinia virus are loaded onto Ni2+ nitriloacetic acid-agarose column and histidine-tagged proteins can be selectively eluted with imidazole-containing buffers.

Fusion Proteins

Any polypeptide of the present invention can be used to generate fusion proteins. For example, the polypeptide of the present invention, when fused to a second protein, can be used as an antigenic tag. Antibodies raised against the polypeptide of the present invention can be used to indirectly detect the second protein by binding to the polypeptide. Moreover, because secreted proteins target cellular locations based on trafficking signals, polypeptides of the present invention which are shown to be secreted can be used as targeting molecules once fused to other proteins.

Examples of domains that can be fused to polypeptides of the present invention include not only heterologous signal sequences, but also other heterologous functional regions. The fusion does not necessarily need to be direct, but may occur through linker sequences.

In certain preferred embodiments, proteins of the invention are fusion proteins comprising an amino acid sequence that is an N and/or C-terminal deletion of a polypeptide of the invention. In preferred embodiments, the invention is directed to a fusion protein comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98% or 99% identical to a polypeptide sequence of the invention. Polynucleotides encoding these proteins are also encompassed by the invention.

Moreover, fusion proteins may also be engineered to improve characteristics of the polypeptide of the present invention. For instance, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence during purification from the host cell or subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification. Such regions may be removed prior to final preparation of the polypeptide. The addition of peptide moieties to facilitate handling of polypeptides are familiar and routine techniques in the art.

As one of skill in the art will appreciate that, as discussed above, polypeptides of the present invention, and epitope-bearing fragments thereof, can be combined with heterologous polypeptide sequences. For example, the polypeptides of the present invention may be fused with heterologous polypeptide sequences, for example, the polypeptides of the present invention may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM) or portions thereof (CH1, CH2, CH3, and any combination thereof, including both entire domains and portions thereof), or albumin (including, but not limited to, native or recombinant human albumin or fragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)), resulting in chimeric polypeptides. For example, EP-A-O 464 533 (Canadian counterpart 2045869) discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties (EP-A 0232 262). Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5. See, D. Bennett et al., J. Molecular Recognition 8:52-58 (1995); K. Johanson et al., J. Biol. Chem. 270:9459-9471 (1995).

Moreover, the polypeptides of the present invention can be fused to marker sequences, such as a polypeptide which facilitates purification of the fused polypeptide. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Another peptide tag useful for purification, the “HA” tag, corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)).

Additional fusion proteins of the invention may be generated through the techniques of gene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling (collectively referred to as “DNA shuffling”). DNA shuffling may be employed to modulate the activities of polypeptides of the invention, such methods can be used to generate polypeptides with altered activity, as well as agonists and antagonists of the polypeptides. See, generally, U.S. Pat. Nos. 5,605,793; 5,811,238; 5,830,721; 5,834,252; and 5,837,458, and Patten et al., Curr. Opinion Biotechnol. 8:724-33 (1997); Harayama, Trends Biotechnol. 16(2):76-82 (1998); Hansson, et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzo and Blasco, Biotechniques 24(2):308-13 (1998) (each of these patents and publications are hereby incorporated by reference in its entirety). In one embodiment, alteration of polynucleotides corresponding to SEQ ID NO:X and the polypeptides encoded by these polynucleotides may be achieved by DNA shuffling. DNA shuffling involves the assembly of two or more DNA segments by homologous or site-specific recombination to generate variation in the polynucleotide sequence. In another embodiment, polynucleotides of the invention, or the encoded polypeptides, may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. In another embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of a polynucleotide encoding a polypeptide of the invention may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.

Thus, any of these above fusions can be engineered using the polynucleotides or the polypeptides of the present invention.

Recombinant and Synthetic Production of Polypeptides of the Invention

The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by synthetic and recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.

The polynucleotides of the invention may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.

As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, G418, glutamine synthase, or neomycin resistance for eukaryotic cell culture, and tetracycline, kanamycin or ampicillin resistance genes for culturing in E. coli and other bacteria. Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as E. coli, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris (ATCC Accession No. 201178)); insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plant cells. Appropriate culture mediums and conditions for the above-described host cells are known in the art.

Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNH8A, pNH16a, pNH18A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Preferred expression vectors for use in yeast systems include, but are not limited to pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, pPIC9K, and PAO815 (all available from Invitrogen, Carlbad, Calif.). Other suitable vectors will be readily apparent to the skilled artisan.

Vectors which use glutamine synthase (GS) or DHFR as the selectable markers can be amplified in the presence of the drugs methionine sulphoximine or methotrexate, respectively. An advantage of glutamine synthase based vectors are the availabilty of cell lines (e.g., the murine myeloma cell line, NSO) which are glutamine synthase negative. Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g., Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene. A glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462; WO86/05807; WO89/01036; WO89/10404; and WO91/06657, which are hereby incorporated in their entireties by reference herein. Additionally, glutamine synthase expression vectors can be obtained from Lonza Biologics, Inc. (Portsmouth, N.H.). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al., Bio/technology 10:169(1992) and in Biblia and Robinson Biotechnol. Prog. 11: 1 (1995) which are herein incorporated by reference.

The present invention also relates to host cells containing the above-described vector constructs described herein, and additionally encompasses host cells containing nucleotide sequences of the invention that are operably associated with one or more heterologous control regions (e.g., promoter and/or enhancer) using techniques known of in the art. The host cell can be a higher eukaryotic cell, such as a mammalian cell (e.g., a human derived cell), or a lower eukaryotic cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. A host strain may be chosen which modulates the expression of the inserted gene sequences, or modifies and processes the gene product in the specific fashion desired. Expression from certain promoters can be elevated in the presence of certain inducers; thus expression of the genetically engineered polypeptide may be controlled. Furthermore, different host cells have characteristics and specific mechanisms for the translational and post-translational processing and modification (e.g., phosphorylation, cleavage) of proteins. Appropriate cell lines can be chosen to ensure the desired modifications and processing of the foreign protein expressed.

Introduction of the nucleic acids and nucleic acid constructs of the invention into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.

In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., the coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous polynucleotide sequences via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication Number WO 96/29411; International Publication Number WO 94/12650; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).

Polypeptides of the invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification.

Polypeptides of the present invention can also be recovered from products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes. Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.

In one embodiment, the yeast Pichia pastoris is used to express polypeptides of the invention in a eukaryotic system. Pichia pastoris is a methylotrophic yeast which can metabolize methanol as its sole carbon source. A main step in the methanol metabolization pathway is the oxidation of methanol to formaldehyde using O₂. This reaction is catalyzed by the enzyme alcohol oxidase. In order to metabolize methanol as its sole carbon source, Pichia pastoris must generate high levels of alcohol oxidase due, in part, to the relatively low affinity of alcohol oxidase for O₂. Consequently, in a growth medium depending on methanol as a main carbon source, the promoter region of one of the two alcohol oxidase genes (AOX1) is highly active. In the presence of methanol, alcohol oxidase produced from the AOX1 gene comprises up to approximately 30% of the total soluble protein in Pichia pastoris. See Ellis, S. B., et al., Mol. Cell. Biol. 5:1111-21 (1985); Koutz, P. J, et al., Yeast 5:167-77 (1989); Tschopp, J. F., et al., Nucl. Acids Res. 15:3859-76 (1987). Thus, a heterologous coding sequence, such as, for example, a polynucleotide of the present invention, under the transcriptional regulation of all or part of the AOX1 regulatory sequence is expressed at exceptionally high levels in Pichia yeast grown in the presence of methanol.

In one example, the plasmid vector pPIC9K is used to express DNA encoding a polypeptide of the invention, as set forth herein, in a Pichea yeast system essentially as described in “Pichia Protocols: Methods in Molecular Biology,” D. R. Higgins and J. Cregg, eds. The Humana Press, Totowa, N.J., 1998. This expression vector allows expression and secretion of a polypeptide of the invention by virtue of the strong AOX1 promoter linked to the Pichia pastoris alkaline phosphatase (PHO) secretory signal peptide (i.e., leader) located upstream of a multiple cloning site.

Many other yeast vectors could be used in place of pPIC9K, such as, pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9, pPIC3.5, pHIL-D2, pHL-S1, pPIC3.5K, and PAO815, as one skilled in the art would readily appreciate, as long as the proposed expression construct provides appropriately located signals for transcription, translation, secretion (if desired), and the like, including an in-frame AUG as required.

In another embodiment, high-level expression of a heterologous coding sequence, such as, for example, a polynucleotide of the present invention, may be achieved by cloning the heterologous polynucleotide of the invention into an expression vector such as, for example, pGAPZ or pGAPZalpha, and growing the yeast culture in the absence of methanol.

In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous polynucleotide sequences via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication No. WO 96/29411, published Sep. 26, 1996; International Publication No. WO 94/12650, published Aug. 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).

In addition, polypeptides of the invention can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, W.H. Freeman & Co., N.Y., and Hunkapiller et al., Nature, 310:105-111 (1984)). For example, a polypeptide corresponding to a fragment of a polypeptide can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the polypeptide sequence. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine, fluoro-amino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary).

The invention encompasses polypeptides of the present invention which are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; etc.

Additional post-translational modifications encompassed by the invention include, for example, e.g., N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of procaryotic host cell expression. The polypeptides may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the protein.

Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include iodine (¹²¹I, ²³¹I, ¹²⁵I, ¹³¹I, carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium (¹¹¹In, ¹¹²In, ^(113m)In, ^(115m)In), technetium (⁹⁹Tc, ^(99m)Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga), palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F), ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, and ⁹⁷Ru.

In specific embodiments, a polypeptide of the present invention or fragment or variant thereof is attached to macrocyclic chelators that associate with radiometal ions, including but not limited to, ¹⁷⁷Lu, ⁹⁰Y, ¹⁶⁶Ho, and ¹⁵³Sm, to polypeptides. In a preferred embodiment, the radiometal ion associated with the macrocyclic chelators is ¹¹¹In. In another preferred embodiment, the radiometal ion associated with the macrocyclic chelator is ⁹⁰Y. In specific embodiments, the macrocyclic chelator is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″-tetraacetic acid (DOTA). In other specific embodiments, DOTA is attached to an antibody of the invention or fragment thereof via a linker molecule. Examples of linker molecules useful for conjugating DOTA to a polypeptide are commonly known in the art—see, for example, DeNardo et al., Clin Cancer Res. 4(10):2483-90 (1998); Peterson et al., Bioconjug. Chem. 10(4):553-7 (1999); and Zimmerman et al, Nucl. Med. Biol. 26(8):943-50 (1999); which are hereby incorporated by reference in their entirety.

As mentioned, the proteins of the invention may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Polypeptides of the invention may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W.H. Freeman and Company, New York (1993); POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-46 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

Also provided by the invention are chemically modified derivatives of the polypeptides of the invention which may provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see U.S. Pat. No. 4,179,337). The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.

The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term “about” indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog). For example, the polyethylene glycol may have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.

As noted above, the polyethylene glycol may have a branched structure. Branched polyethylene glycols are described, for example, in U.S. Pat. No. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol. 56:59-72 (1996); Vorobjev et al., Nucleosides Nucleotides 18:2745-2750 (1999); and Caliceti et al., Bioconjug. Chem. 10:638-646 (1999), the disclosures of each of which are incorporated herein by reference.

The polyethylene glycol molecules (or other chemical moieties) should be attached to the protein with consideration of effects on functional or antigenic domains of the protein. There are a number of attachment methods available to those skilled in the art, such as, for example, the method disclosed in EP 0 401 384 (coupling PEG to G-CSF), herein incorporated by reference; see also Malik et al., Exp. Hematol. 20:1028-1035 (1992), reporting pegylation of GM-CSF using tresyl chloride. For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group.

As suggested above, polyethylene glycol may be attached to proteins via linkage to any of a number of amino acid residues. For example, polyethylene glycol can be linked to proteins via covalent bonds to lysine, histidine, aspartic acid, glutamic acid, or cysteine residues. One or more reaction chemistries may be employed to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine) of the protein or to more than one type of amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine and combinations thereof) of the protein.

One may specifically desire proteins chemically modified at the N-terminus. Using polyethylene glycol as an illustration of the present composition, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, etc.), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N-terminus modification may be accomplished by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.

As indicated above, pegylation of the proteins of the invention may be accomplished by any number of means. For example, polyethylene glycol may be attached to the protein either directly or by an intervening linker. Linkerless systems for attaching polyethylene glycol to proteins are described in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992); Francis et al., Intern. J. of Hematol. 68:1-18 (1998); U.S. Pat. No. 4,002,531; U.S. Pat. No. 5,349,052; WO 95/06058; and WO 98/32466, the disclosures of each of which are incorporated herein by reference.

One system for attaching polyethylene glycol directly to amino acid residues of proteins without an intervening linker employs tresylated MPEG, which is produced by the modification of monmethoxy polyethylene glycol (MPEG) using tresylchloride (ClSO₂CH₂CF₃). Upon reaction of protein with tresylated MPEG, polyethylene glycol is directly attached to amine groups of the protein. Thus, the invention includes protein-polyethylene glycol conjugates produced by reacting proteins of the invention with a polyethylene glycol molecule having a 2,2,2-trifluoreothane sulphonyl group.

Polyethylene glycol can also be attached to proteins using a number of different intervening linkers. For example, U.S. Pat. No. 5,612,460, the entire disclosure of which is incorporated herein by reference, discloses urethane linkers for connecting polyethylene glycol to proteins. Protein-polyethylene glycol conjugates wherein the polyethylene glycol is attached to the protein by a linker can also be produced by reaction of proteins with compounds such as MPEG-succinimidylsuccinate, MPEG activated with 1,1′-carbonyldiimidazole, MPEG-2,4,5-trichloropenylcarbonate, MPEG-p-nitrophenolcarbonate, and various MPEG-succinate derivatives. A number of additional polyethylene glycol derivatives and reaction chemistries for attaching polyethylene glycol to proteins are described in International Publication No. WO 98/32466, the entire disclosure of which is incorporated herein by reference. Pegylated protein products produced using the reaction chemistries set out herein are included within the scope of the invention.

The number of polyethylene glycol moieties attached to each protein of the invention (i.e., the degree of substitution) may also vary. For example, the pegylated proteins of the invention may be linked, on average, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, or more polyethylene glycol molecules. Similarly, the average degree of substitution within ranges such as 1-3, 3-5, 4-6, 6-8, 8-10, 9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19, or 18-20 polyethylene glycol moieties per protein molecule. Methods for determining the degree of substitution are discussed, for example, in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992).

The polypeptides of the invention can be recovered and purified from chemical synthesis and recombinant cell cultures by standard methods which include, but are not limited to, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification. Well known techniques for refolding protein may be employed to regenerate active conformation when the polypeptide is denatured during isolation and/or purification.

The polypeptides of the invention may be in monomers or multimers (i.e., dimers, trimers, tetramers and higher multimers). Accordingly, the present invention relates to monomers and multimers of the polypeptides of the invention, their preparation, and compositions (preferably, Therapeutics) containing them. In specific embodiments, the polypeptides of the invention are monomers, dimers, trimers or tetramers. In additional embodiments, the multimers of the invention are at least dimers, at least trimers, or at least tetramers.

Multimers encompassed by the invention may be homomers or heteromers. As used herein, the term homomer refers to a multimer containing only polypeptides corresponding to a protein of the invention (e.g., the amino acid sequence of SEQ ID NO:Y, an amino acid sequence encoded by SEQ ID NO:X or the complement of SEQ ID NO:X, the amino acid sequence encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/or an amino acid sequence encoded by cDNA contained in ATCC Deposit No:Z (including fragments, variants, splice variants, and fusion proteins, corresponding to these as described herein)). These homomers may contain polypeptides having identical or different amino acid sequences. In a specific embodiment, a homomer of the invention is a multimer containing only polypeptides having an identical amino acid sequence. In another specific embodiment, a homomer of the invention is a multimer containing polypeptides having different amino acid sequences. In specific embodiments, the multimer of the invention is a homodimer (e.g., containing two polypeptides having identical or different amino acid sequences) or a homotrimer (e.g., containing three polypeptides having identical and/or different amino acid sequences). In additional embodiments, the homomeric multimer of the invention is at least a homodimer, at least a homotrimer, or at least a homotetramer.

As used herein, the term heteromer refers to a multimer containing one or more heterologous polypeptides (i.e., polypeptides of different proteins) in addition to the polypeptides of the invention. In a specific embodiment, the multimer of the invention is a heterodimer, a heterotrimer, or a heterotetramer. In additional embodiments, the heteromeric multimer of the invention is at least a heterodimer, at least a heterotramer, or at least a heterotetramer.

Multimers of the invention may be the result of hydrophobic, hydrophilic, ionic and/or covalent associations and/or may be indirectly linked by, for example, liposome formation. Thus, in one embodiment, multimers of the invention, such as, for example, homodimers or homotrimers, are formed when polypeptides of the invention contact one another in solution. In another embodiment, heteromultimers of the invention, such as, for example, heterotrimers or heterotetramers, are formed when polypeptides of the invention contact antibodies to the polypeptides of the invention (including antibodies to the heterologous polypeptide sequence in a fusion protein of the invention) in solution. In other embodiments, multimers of the invention are formed by covalent associations with and/or between the polypeptides of the invention. Such covalent associations may involve one or more amino acid residues contained in the polypeptide sequence (e.g., that recited in SEQ ID NO:Y, encoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/or encoded by the cDNA contained in ATCC Deposit No:Z). In one instance, the covalent associations are cross-linking between cysteine residues located within the polypeptide sequences which interact in the native (i.e., naturally occurring) polypeptide. In another instance, the covalent associations are the consequence of chemical or recombinant manipulation. Alternatively, such covalent associations may involve one or more amino acid residues contained in the heterologous polypeptide sequence in a fusion protein. In one example, covalent associations are between the heterologous sequence contained in a fusion protein of the invention (see, e.g., U.S. Pat. No. 5,478,925). In a specific example, the covalent associations are between the heterologous sequence contained in a Fc fusion protein of the invention (as described herein). In another specific example, covalent associations of fusion proteins of the invention are between heterologous polypeptide sequence from another protein that is capable of forming covalently associated multimers, such as for example, osteoprotegerin (see, e.g., International Publication NO: WO 98/49305, the contents of which are herein incorporated by reference in its entirety). In another embodiment, two or more polypeptides of the invention are joined through peptide linkers. Examples include those peptide linkers described in U.S. Pat. No. 5,073,627 (hereby incorporated by reference). Proteins comprising multiple polypeptides of the invention separated by peptide linkers may be produced using conventional recombinant DNA technology.

Another method for preparing multimer polypeptides of the invention involves use of polypeptides of the invention fused to a leucine zipper or isoleucine zipper polypeptide sequence. Leucine zipper and isoleucine zipper domains are polypeptides that promote multimerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA-binding proteins (Landschulz et al., Science 240:1759, (1988)), and have since been found in a variety of different proteins. Among the known leucine zippers are naturally occurring peptides and derivatives thereof that dimerize or trimerize. Examples of leucine zipper domains suitable for producing soluble multimeric proteins of the invention are those described in PCT application WO 94/10308, hereby incorporated by reference. Recombinant fusion proteins comprising a polypeptide of the invention fused to a polypeptide sequence that dimerizes or trimerizes in solution are expressed in suitable host cells, and the resulting soluble multimeric fusion protein is recovered from the culture supernatant using techniques known in the art.

Trimeric polypeptides of the invention may offer the advantage of enhanced biological activity. Preferred leucine zipper moieties and isoleucine moieties are those that preferentially form trimers. One example is a leucine zipper derived from lung surfactant protein D (SPD), as described in Hoppe et al. (FEBS Letters 344:191, (1994)) and in U.S. patent application Ser. No. 08/446,922, hereby incorporated by reference. Other peptides derived from naturally occurring trimeric proteins may be employed in preparing trimeric polypeptides of the invention.

In another example, proteins of the invention are associated by interactions between Flag® polypeptide sequence contained in fusion proteins of the invention containing Flag® polypeptide sequence. In a further embodiment, proteins of the invention are associated by interactions between heterologous polypeptide sequence contained in Flag® fusion proteins of the invention and anti-Flag® antibody.

The multimers of the invention may be generated using chemical techniques known in the art. For example, polypeptides desired to be contained in the multimers of the invention may be chemically cross-linked using linker molecules and linker molecule length optimization techniques known in the art (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Additionally, multimers of the invention may be generated using techniques known in the art to form one or more inter-molecule cross-links between the cysteine residues located within the sequence of the polypeptides desired to be contained in the multimer (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Further, polypeptides of the invention may be routinely modified by the addition of cysteine or biotin to the C-terminus or N-terminus of the polypeptide and techniques known in the art may be applied to generate multimers containing one or more of these modified polypeptides (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Additionally, techniques known in the art may be applied to generate liposomes containing the polypeptide components desired to be contained in the multimer of the invention (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety).

Alternatively, multimers of the invention may be generated using genetic engineering techniques known in the art. In one embodiment, polypeptides contained in multimers of the invention are produced recombinantly using fusion protein technology described herein or otherwise known in the art (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). In a specific embodiment, polynucleotides coding for a homodimer of the invention are generated by ligating a polynucleotide sequence encoding a polypeptide of the invention to a sequence encoding a linker polypeptide and then further to a synthetic polynucleotide encoding the translated product of the polypeptide in the reverse orientation from the original C-terminus to the N-terminus (lacking the leader sequence) (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). In another embodiment, recombinant techniques described herein or otherwise known in the art are applied to generate recombinant polypeptides of the invention which contain a transmembrane domain (or hydrophobic or signal peptide) and which can be incorporated by membrane reconstitution techniques into liposomes (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety).

Antibodies

Further polypeptides of the invention relate to antibodies and T-cell antigen receptors (TCR) which immunospecifically bind a polypeptide, polypeptide fragment, or variant of the invention (e.g., a polypeptide or fragment or variant of the amino acid sequence of SEQ ID NO:Y or a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/or an epitope, of the present invention) as determined by immunoassays well known in the art for assaying specific antibody-antigen binding. Antibodies of the invention include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′) fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), intracellularly-made antibodies (i.e., intrabodies), and epitope-binding fragments of any of the above. The term “antibody,” as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen. The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. In preferred embodiments, the immunoglobulin molecules of the invention are IgG1. In other preferred embodiments, the immunoglobulin molecules of the invention are IgG4.

Most preferably the antibodies are human antigen-binding antibody fragments of the present invention and include, but are not limited to, Fab, Fab′ and F(ab′)2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH2, and CH3 domains. Also included in the invention are antigen-binding fragments also comprising any combination of variable region(s) with a hinge region, CH1, CH2, and CH3 domains. The antibodies of the invention may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, ship rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulin and that do not express endogenous immunoglobulins, as described infra and, for example in, U.S. Pat. No. 5,939,598 by Kucherlapati et al.

The antibodies of the present invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol. 148:1547-1553 (1992).

Antibodies of the present invention may be described or specified in terms of the epitope(s) or portion(s) of a polypeptide of the present invention which they recognize or specifically bind. The epitope(s) or polypeptide portion(s) may be specified as described herein, e.g., by N-terminal and C-terminal positions, or by size in contiguous amino acid residues, or listed in the Tables and Figures. Preferred epitopes of the invention include the predicted epitopes shown in Table 1B, as well as polynucleotides that encode these epitopes. Antibodies which specifically bind any epitope or polypeptide of the present invention may also be excluded. Therefore, the present invention includes antibodies that specifically bind polypeptides of the present invention, and allows for the exclusion of the same.

Antibodies of the present invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not bind any other analog, ortholog, or homolog of a polypeptide of the present invention are included. Antibodies that bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In specific embodiments, antibodies of the present invention cross-react with murine, rat and/or rabbit homologs of human proteins and the corresponding epitopes thereof. Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In a specific embodiment, the above-described cross-reactivity is with respect to any single specific antigenic or immunogenic polypeptide, or combination(s) of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenic polypeptides disclosed herein. Further included in the present invention are antibodies which bind polypeptides encoded by polynucleotides which hybridize to a polynucleotide of the present invention under stringent hybridization conditions (as described herein). Antibodies of the present invention may also be described or specified in terms of their binding affinity to a polypeptide of the invention. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10⁻² M, 10⁻²M, 5×10⁻³ M, 10⁻³ M, 5×10⁻⁴ M, 10⁻⁴ M, 5×10⁻⁵ M, 10⁻⁵ M, 5×10⁻⁶ M, 10⁻⁶M, 5×10⁻⁷ M, 10⁷ M, 5×10⁻⁸M, 10⁻⁸ M, 5×10⁻⁹ M, 10⁻⁹ M, 5×10⁻¹⁰ M, 10⁻¹⁰ M, 5×10⁻¹¹M, 10⁻¹¹ M, 5×10⁻¹² M, 10⁻¹² M, 5×10⁻¹³ M, 10⁻¹³ M, 5×10⁻¹⁴ M, 10⁻¹⁴ M, 5×10⁻¹⁵ M, or 10⁻¹⁵ M.

The invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of the invention as determined by any method known in the art for determining competitive binding, for example, the immunoassays described herein. In preferred embodiments, the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.

Antibodies of the present invention may act as agonists or antagonists of the polypeptides of the present invention. For example, the present invention includes antibodies which disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully. Preferably, antibodies of the present invention bind an antigenic epitope disclosed herein, or a portion thereof. The invention features both receptor-specific antibodies and ligand-specific antibodies. The invention also features receptor-specific antibodies which do not prevent ligand binding but prevent receptor activation. Receptor activation (i.e., signaling) may be determined by techniques described herein or otherwise known in the art. For example, receptor activation can be determined by detecting the phosphorylation (e.g., tyrosine or serine/threonine) of the receptor or its substrate by immunoprecipitation followed by western blot analysis (for example, as described supra). In specific embodiments, antibodies are provided that inhibit ligand activity or receptor activity by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50% of the activity in absence of the antibody.

The invention also features receptor-specific antibodies which both prevent ligand binding and receptor activation as well as antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand. Likewise, included in the invention are neutralizing antibodies which bind the ligand and prevent binding of the ligand to the receptor, as well as antibodies which bind the ligand, thereby preventing receptor activation, but do not prevent the ligand from binding the receptor. Further included in the invention are antibodies which activate the receptor. These antibodies may act as receptor agonists, i.e., potentiate or activate either all or a subset of the biological activities of the ligand-mediated receptor activation, for example, by inducing dimerization of the receptor. The antibodies may be specified as agonists, antagonists or inverse agonists for biological activities comprising the specific biological activities of the peptides of the invention disclosed herein. The above antibody agonists can be made using methods known in the art. See, e.g., PCT publication WO 96/40281; U.S. Pat. No. 5,811,097; Deng et al., Blood 92(6):1981-1988 (1998); Chen et al., Cancer Res. 58(16):3668-3678 (1998); Harrop et al., J. Immunol. 161(4):1786-1794 (1998); Zhu et al., Cancer Res. 58(15):3209-3214 (1998); Yoon et al., J. Immunol. 160(7):3170-3179 (1998); Prat et al., J. Cell. Sci. 111(Pt2):237-247 (1998); Pitard et al., J. Immunol. Methods 205(2):177-190 (1997); Liautard et al., Cytokine 9(4):233-241 (1997); Carlson et al., J. Biol. Chem. 272(17):11295-11301 (1997); Taryman et al., Neuron 14(4):755-762 (1995); Muller et al., Structure 6(9):1153-1167 (1998); Bartunek et al., Cytokine 8(1):14-20 (1996) (which are all incorporated by reference herein in their entireties).

Antibodies of the present invention may be used, for example, to purify, detect, and target the polypeptides of the present invention, including both in vitro and in vivo diagnostic and therapeutic methods. For example, the antibodies have utility in immunoassays for qualitatively and quantitatively measuring levels of the polypeptides of the present invention in biological samples. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); incorporated by reference herein in its entirety.

As discussed in more detail below, the antibodies of the present invention may be used either alone or in combination with other compositions. The antibodies may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalent and non-covalent conjugations) to polypeptides or other compositions. For example, antibodies of the present invention may be recombinantly fused or conjugated to molecules useful as labels in detection assays and effector molecules such as heterologous polypeptides, drugs, radionuclides, or toxins. See, e.g., PCT publications WO 92/08495; WO 91/14438; WO 89/12624; U.S. Pat. No. 5,314,995; and EP 396,387; the disclosures of which are incorporated herein by reference in their entireties.

The antibodies of the invention include derivatives that are modified, i.e, by the covalent attachment of any type of molecule to the antibody such that covalent attachment does not prevent the antibody from generating an anti-idiotypic response. For example, but not by way of limitation, the antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-classical amino acids.

The antibodies of the present invention may be generated by any suitable method known in the art. Polyclonal antibodies to an antigen-of-interest can be produced by various procedures well known in the art. For example, a polypeptide of the invention can be administered to various host animals including, but not limited to, rabbits, mice, rats, etc. to induce the production of sera containing polyclonal antibodies specific for the antigen. Various adjuvants may be used to increase the immunological response, depending on the host species, and include but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum. Such adjuvants are also well known in the art.

Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling, et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981) (said references incorporated by reference in their entireties). The term “monoclonal antibody” as used herein is not limited to antibodies produced through hybridoma technology. The term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.

Methods for producing and screening for specific antibodies using hybridoma technology are routine and well known in the art and are discussed in detail in the Examples. In a non-limiting example, mice can be immunized with a polypeptide of the invention or a cell expressing such peptide. Once an immune response is detected, e.g., antibodies specific for the antigen are detected in the mouse serum, the mouse spleen is harvested and splenocytes isolated. The splenocytes are then fused by well known techniques to any suitable myeloma cells, for example cells from cell line SP20 available from the ATCC. Hybridomas are selected and cloned by limited dilution. The hybridoma clones are then assayed by methods known in the art for cells that secrete antibodies capable of binding a polypeptide of the invention. Ascites fluid, which generally contains high levels of antibodies, can be generated by immunizing mice with positive hybridoma clones.

Accordingly, the present invention provides methods of generating monoclonal antibodies as well as antibodies produced by the method comprising culturing a hybridoma cell secreting an antibody of the invention wherein, preferably, the hybridoma is generated by fusing splenocytes isolated from a mouse immunized with an antigen of the invention with myeloma cells and then screening the hybridomas resulting from the fusion for hybridoma clones that secrete an antibody able to bind a polypeptide of the invention.

Another well known method for producing both polyclonal and monoclonal human B cell lines is transformation using Epstein Barr Virus (EBV). Protocols for generating EBV-transformed B cell lines are commonly known in the art, such as, for example, the protocol outlined in Chapter 7.22 of Current Protocols in Immunology, Coligan et al., Eds., 1994, John Wiley & Sons, NY, which is hereby incorporated in its entirety by reference. The source of B cells for transformation is commonly human peripheral blood, but B cells for transformation may also be derived from other sources including, but not limited to, lymph nodes, tonsil, spleen, tumor tissue, and infected tissues. Tissues are generally made into single cell suspensions prior to EBV transformation. Additionally, steps may be taken to either physically remove or inactivate T cells (e.g., by treatment with cyclosporin A) in B cell-containing samples, because T cells from individuals seropositive for anti-EBV antibodies can suppress B cell immortalization by EBV.

In general, the sample containing human B cells is innoculated with EBV, and cultured for 3-4 weeks. A typical source of EBV is the culture supernatant of the B95-8 cell line (ATCC #VR-1492). Physical signs of EBV transformation can generally be seen towards the end of the 3-4 week culture period. By phase-contrast microscopy, transformed cells may appear large, clear, hairy and tend to aggregate in tight clusters of cells. Initially, EBV lines are generally polyclonal. However, over prolonged periods of cell cultures, EBV lines may become monoclonal or polyclonal as a result of the selective outgrowth of particular B cell clones. Alternatively, polyclonal EBV transformed lines may be subcloned (e.g., by limiting dilution culture) or fused with a suitable fusion partner and plated at limiting dilution to obtain monoclonal B cell lines. Suitable fusion partners for EBV transformed cell lines include mouse myeloma cell lines (e.g., SP2/0, X63-Ag8.653), heteromyeloma cell lines (human×mouse; e.g, SPAM-8, SBC-H20, and CB-F7), and human cell lines (e.g., GM 1500, SKO-007, RPMI 8226, and KR-4). Thus, the present invention also provides a method of generating polyclonal or monoclonal human antibodies against polypeptides of the invention or fragments thereof, comprising EBV-transformation of human B cells.

Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, Fab and F(ab′)2 fragments of the invention may be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab′)2 fragments). F(ab′)2 fragments contain the variable region, the light chain constant region and the CH1 domain of the heavy chain.

For example, the antibodies of the present invention can also be generated using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them. In a particular embodiment, such phage can be utilized to display antigen binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine). Phage expressing an antigen binding domain that binds the antigen of interest can be selected or identified with antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 binding domains expressed from phage with Fab, Fv or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. Examples of phage display methods that can be used to make the antibodies of the present invention include those disclosed in Brinkan et al., J. Immunol. Methods 182:41-50 (1995); Ames et al., J. Immunol. Methods 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol. 24:952-958 (1994); Persic et al., Gene 187 9-18 (1997); Burton et al., Advances in Immunology 57:191-280 (1994); PCT application No. PCT/GB91/01134; PCT” publications WO 90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108; each of which is incorporated herein by reference in its entirety.

As described in the above references, after phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, e.g., as described in detail below. For example, techniques to recombinantly produce Fab, Fab′ and F(ab′)2 fragments can also be employed using methods known in the art such as those disclosed in PCT publication WO 92/22324; Mullinax et al., BioTechniques 12(6):864-869 (1992); and Sawai et al., AJRI 34:26-34 (1995); and Better et al., Science 240:1041-1043 (1988) (said references incorporated by reference in their entireties).

Examples of techniques which can be used to produce single-chain Fvs and antibodies include those described in U.S. Pat. Nos. 4,946,778 and 5,258,498; Huston et al., Methods in Enzymology 203:46-88 (1991); Shu et al., PNAS 90:7995-7999 (1993); and Skerra et al., Science 240:1038-1040 (1988). For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Gillies et al., (1989) J. Immunol. Methods 125:191-202; U.S. Pat. Nos. 5,807,715; 4,816,567; and 4,816397, which are incorporated herein by reference in their entirety. Humanized antibodies are antibody molecules from non-human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and a framework regions from a human immunoglobulin molecule. Often, framework residues in the human framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding. These framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmann et al., Nature 332:323 (1988), which are incorporated herein by reference in their entireties.) Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91/09967; U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, Molecular Immunology 28(4/5):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., PNAS 91:969-973 (1994)), and chain shuffling (U.S. Pat. No. 5,565,332).

Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also, U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated herein by reference in its entirety.

Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. For example, the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes. The mouse heavy and light chain immunoglobulin genes may be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JH region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring which express human antibodies. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention. Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar, Int. Rev. Immunol. 13:65-93 (1995). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; 5,939,598; 6,075,181; and 6,114,598, which are incorporated by reference herein in their entirety. In addition, companies such as Abgenix, Inc. (Freemont, Calif.) and Genpharm (San Jose, Calif.) can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.

Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as “guided selection.” In this approach a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope. (Jespers et al., Bio/technology 12:899-903 (1988)).

Further, antibodies to the polypeptides of the invention can, in turn, be utilized to generate anti-idiotype antibodies that “mimic” polypeptides of the invention using techniques well known to those skilled in the art. (See, e.g., Greenspan & Bona, FASEB J. 7(5):437-444; (1989) and Nissinoff, J. Immunol. 147(8):2429-2438 (1991)). For example, antibodies which bind to and competitively inhibit polypeptide multimerization and/or binding of a polypeptide of the invention to a ligand can be used to generate anti-idiotypes that “mimic” the polypeptide multimerization and/or binding domain and, as a consequence, bind to and neutralize polypeptide and/or its ligand. Such neutralizing anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens to neutralize polypeptide ligand(s)/receptor(s). For example, such anti-idiotypic antibodies can be used to bind a polypeptide of the invention and/or to bind its ligand(s)/receptor(s), and thereby block its biological activity. Alternatively, antibodies which bind to and enhance polypeptide multimerization and/or binding, and/or receptor/ligand multimerization, binding and/or signaling can be used to generate anti-idiotypes that function as agonists of a polypeptide of the invention and/or its ligand/receptor. Such agonistic anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens as agonists of the polypeptides of the invention or its ligand(s)/receptor(s). For example, such anti-idiotypic antibodies can be used to bind a polypeptide of the invention and/or to bind its ligand(s)/receptor(s), and thereby promote or enhance its biological activity.

Intrabodies of the invention can be produced using methods known in the art, such as those disclosed and reviewed in Chen et al., Hum. Gene Ther. 5:595-601 (1994); Marasco, W. A., Gene Ther. 4:11-15 (1997); Rondon and Marasco, Annu. Rev. Microbiol. 51:257-283 (1997); Proba et al., J. Mol. Biol. 275:245-253 (1998); Cohen et al., Oncogene 17:2445-2456 (1998); Ohage and Steipe, J. Mol. Biol. 291:1119-1128 (1999); Ohage et al., J. Mol. Biol. 291:1129-1134 (1999); Wirtz and Steipe, Protein Sci. 8:2245-2250 (1999); Zhu et al., J. Immunol. Methods 231:207-222 (1999); and references cited therein.

Polynucleotides Encoding Antibodies

The invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody of the invention and fragments thereof. The invention also encompasses polynucleotides that hybridize under stringent or alternatively, under lower stringency hybridization conditions, e.g., as defined supra, to polynucleotides that encode an antibody, preferably, that specifically binds to a polypeptide of the invention, preferably, an antibody that binds to a polypeptide having the amino acid sequence of SEQ ID NO:Y, to a polypeptide encoded by a portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/or to a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

The polynucleotides may be obtained, and the nucleotide sequence of the polynucleotides determined, by any method known in the art For example, if the nucleotide sequence of the antibody is known, a polynucleotide encoding the antibody may be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., BioTechniques 17:242 (1994)), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.

Alternatively, a polynucleotide encoding an antibody may be generated from nucleic acid from a suitable source. If a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin may be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library, or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody of the invention) by PCR amplification using synthetic primers hybridizable to the 3′ and 5′ ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by PCR may then be cloned into replicable cloning vectors using any method well known in the art.

Once the nucleotide sequence and corresponding amino acid sequence of the antibody is determined, the nucleotide sequence of the antibody may be manipulated using methods well known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Sambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. and Ausubel et al., eds., 1998, Current Protocols in Molecular Biology, John Wiley & Sons, NY, which are both incorporated by reference herein in their entireties), to generate antibodies having a different amino acid sequence, for example to create amino acid substitutions, deletions, and/or insertions.

In a specific embodiment, the amino acid sequence of the heavy and/or light chain variable domains may be inspected to identify the sequences of the complementarity determining regions (CDRs) by methods that are well know in the art, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. Using routine recombinant DNA techniques, one or more of the CDRs may be inserted within framework regions, e.g., into human framework regions to humanize a non-human antibody, as described supra. The framework regions may be naturally occurring or consensus framework regions, and preferably human framework regions (see, e.g., Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for a listing of human framework regions). Preferably, the polynucleotide generated by the combination of the framework regions and CDRs encodes an antibody that specifically binds a polypeptide of the invention. Preferably, as discussed supra, one or more amino acid substitutions may be made within the framework regions, and, preferably, the amino acid substitutions improve binding of the antibody to its antigen. Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody molecules lacking one or more intrachain disulfide bonds. Other alterations to the polynucleotide are encompassed by the present invention and within the skill of the art.

In addition, techniques developed for the production of “chimeric antibodies” (Morrison et al., Proc. Natl. Acad. Sci. 81:851-855 (1984); Neuberger et al., Nature 312:604-608 (1984); Takeda et al., Nature 314:452-454 (1985)) by splicing genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. As described supra, a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region, e.g., humanized antibodies.

Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778; Bird, Science 242:423-42 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Ward et al., Nature 334:544-54 (1989)) can be adapted to produce single chain antibodies. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide. Techniques for the assembly of functional Fv fragments in E. coli may also be used (Skerra et al., Science 242:1038-1041 (1988)).

Methods of Producing Antibodies

The antibodies of the invention can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques. Methods of producing antibodies include, but are not limited to, hybridoma technology, EBV transformation, and other methods discussed herein as well as through the use recombinant DNA technology, as discussed below.

Recombinant expression of an antibody of the invention, or fragment, derivative or analog thereof, (e.g., a heavy or light chain of an antibody of the invention or a single chain antibody of the invention), requires construction of an expression vector containing a polynucleotide that encodes the antibody. Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the invention, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.

The expression vector is transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody of the invention. Thus, the invention includes host cells containing a polynucleotide encoding an antibody of the invention, or a heavy or light chain thereof, or a single chain antibody of the invention, operably linked to a heterologous promoter. In preferred embodiments for the expression of double-chained antibodies, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to express the antibody molecules of the invention. Such host-expression systeins represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from rnammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 (1990)).

In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the antibody molecule being expressed. For example, when a large quantity of such a protein is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the E. coli expression vector pUR278 (Ruther et al., EMBO J. 2:1791 (1983)), in which the antibody coding sequence may be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, Nucleic Acids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem. 24:5503-5509 (1989)); and the like. pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione-agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The antibody coding sequence may be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).

In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the antibody coding sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts. (e.g., see Logan & Shenk, Proc. Natl. Acad. Sci. USA 81:355-359 (1984)). Specific initiation signals may also be required for efficient translation of inserted antibody coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see Bittner et al., Methods in Enzymol. 153:51-544 (1987)).

In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include but are not limited to CHO, VERY, BHK, Hela, COS, MDCK, 293, 3T3, WI38, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary gland cell line such as, for example, CRL7030 and Hs578Bst.

For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the antibody molecule may be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express the antibody molecule. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that interact directly or indirectly with the antibody molecule.

A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell 22:817 (1980)) genes can be employed in tk-, hgprt- or aprt-cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 Clinical Pharmacy 12:488-505; Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, 1993, TIB TECH 11(5):155-215 (1993)); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30:147 (1984)). Methods commonly known in the art of recombinant DNA technology may be routinely applied to select the desired recombinant clone, and such methods are described, for example, in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981), which are incorporated by reference herein in their entireties.

The expression levels of an antibody molecule can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol. 3. (Academic Press, New York, 1987)). When a marker in the vector system expressing antibody is amplifiable, increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the antibody gene, production of the antibody will also increase (Crouse et al., Mol. Cell. Biol. 3:257 (1983)).

Vectors which use glutamine synthase (GS) or DHFR as the selectable markers can be amplified in the presence of the drugs methionine sulphoximine or methotrexate, respectively. An advantage of glutamine synthase based vectors are the availabilty of cell lines (e.g., the murine myeloma cell line, NSO) which are glutamine synthase negative. Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g. Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene. A glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462; WO86/05807; WO89/01036; WO89/10404; and WO91/06657 which are incorporated in their entireties by reference herein. Additionally, glutamine synthase expression vectors that may be used according to the present invention are commercially available from suplliers, including, for example Lonza Biologics, Inc. (Portsmouth, N.H.). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al., Bio/technology 10:169(1992) and in Biblia and Robinson Biotechnol. Prog. 11:1 (1995) which are incorporated in their entirities by reference herein.

The host cell may be co-transfected with two expression vectors of the invention, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. Alternatively, a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc. Natl. Acad. Sci. USA 77:2197 (1980)). The coding sequences for the heavy and light chains may comprise cDNA or genomic DNA.

Once an antibody molecule of the invention has been produced by an animal, chemically synthesized, or recombinantly expressed, it may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. In addition, the antibodies of the present invention or fragments thereof can be fused to heterologous polypeptide sequences described herein or otherwise known in the art, to facilitate purification.

The present invention encompasses antibodies recombinantly fused or chemically conjugated (including both covalently and non-covalently conjugations) to a polypeptide (or portion thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention to generate fusion proteins. The fusion does not necessarily need to be direct, but may occur through linker sequences. The antibodies may be specific for antigens other than polypeptides (or portion thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention. For example, antibodies may be used to target the polypeptides of the present invention to particular cell types, either in vitro or in vivo, by fusing or conjugating the polypeptides of the present invention to antibodies specific for particular cell surface receptors. Antibodies fused or conjugated to the polypeptides of the present invention may also be used in in vitro immunoassays and purification methods using methods known in the art. See e.g., Harbor et al., supra, and PCT publication WO 93/21232; EP 439,095; Naramura et al., Immunol. Lett. 39:91-99 (1994); U.S. Pat. No. 5,474,981; Gillies et al., PNAS 89:1428-1432 (1992); Fell et al., J. Immunol. 146:2446-2452 (1991), which are incorporated by reference in their entireties.

The present invention further includes compositions comprising the polypeptides of the present invention fused or conjugated to antibody domains other than the variable regions. For example, the polypeptides of the present invention may be fused or conjugated to an antibody Fc region, or portion thereof. The antibody portion fused to a polypeptide of the present invention may comprise the constant region, hinge region, CH1 domain, CH2 domain, and CH3 domain or any combination of whole domains or portions thereof. The polypeptides may also be fused or conjugated to the above antibody portions to form multimers. For example, Fc portions fused to the polypeptides of the present invention can form dimers through disulfide bonding between the Fc portions. Higher multimeric forms can be made by fusing the polypeptides to portions of IgA and IgM. Methods for fusing or conjugating the polypeptides of the present invention to antibody portions are known in the art. See, e.g., U.S. Pat. Nos. 5,336,603; 5,622,929; 5,359,046; 5,349,053; 5,447,851; 5,112,946; EP 307,434; EP 367,166; PCT publications WO 96/04388; WO 91/06570; Ashkenazi et al., Proc. Natl. Acad. Sci. USA 88:10535-10539 (1991); Zheng et al., J. Immunol. 154:5590-5600 (1995); and Vil et al., Proc. Natl. Acad. Sci. USA 89:11337-11341 (1992) (said references incorporated by reference in their entireties).

As discussed, supra, the polypeptides corresponding to a polypeptide, polypeptide fragment, or a variant of SEQ ID NO:Y may be fused or conjugated to the above antibody portions to increase the in vivo half life of the polypeptides or for use in immunoassays using methods known in the art. Further, the polypeptides corresponding to SEQ ID NO:Y may be fused or conjugated to the above antibody portions to facilitate purification. One reported example describes chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See EP 394,827; and Traunecker et al., Nature 331:84-86 (1988). The polypeptides of the present invention fused or conjugated to an antibody having disulfide-linked dimeric structures (due to the IgG) may also be more efficient in binding and neutralizing other molecules, than the monomeric secreted protein or protein fragment alone. See, for example, Fountoulakis et al., J. Biochem. 270:3958-3964 (1995). In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties. See, for example, EP A 232,262. Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Pc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5. (See, Bennett et al., J. Molecular Recognition 8:52-58 (1995); Johanson et al., J. Biol. Chem. 270:9459-9471 (1995)).

Moreover, the antibodies or fragments thereof of the present invention can be fused to marker sequences, such as a peptide to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the “HA” tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)) and the “flag” tag.

The present invention further encompasses antibodies or fragments thereof conjugated to a diagnostic or therapeutic agent. The antibodies can be used diagnostically to, for example, monitor the development or progression of a tumor as part of a clinical testing procedure to, e.g., determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting metals using various positron emission tomographies, and nonradioactive paramagnetic metal ions. The detectable substance may be coupled or conjugated either directly to the antibody (or fragment thereof) or indirectly, through an intermediate (such as, for example, a linker known in the art) using techniques known in the art. See, for example, U.S. Pat. No. 4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics according to the present invention. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include 125I, 131I, 111In or 99Tc.

Further, an antibody or fragment thereof may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).

The conjugates of the invention can be used for modifying a given biological response, the therapeutic agent or drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, a-interferon, 13-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See, International Publication No. WO 97/33899), AIM II (See, International Publication No. WO 97/34911), Fas Ligand (Takahashi et al., Int. Immunol., 6:1567-1574 (1994)), VEGI (See, International Publication No. WO 99/23105), a thrombotic agent or an anti-angiogenic agent, e.g., angiostatin or endostatin; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.

Antibodies may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.

Techniques for conjugating such therapeutic moiety to antibodies are well known. See, for example, Amon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”, Immunol. Rev. 62:119-58 (1982).

Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980, which is incorporated herein by reference in its entirety.

An antibody, with or without a therapeutic moiety conjugated to it, administered alone or in combination with cytotoxic factor(s) and/or cytokine(s) can be used as a therapeutic.

Immunophenotyping

The antibodies of the invention may be utilized for immunophenotyping of cell lines and biological samples. Translation products of the gene of the present invention may be useful as cell-specific markers, or more specifically as cellular markers that are differentially expressed at various stages of differentiation and/or maturation of particular cell types. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the screening of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, “panning” with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No. 5,985,660; and Morrison et al., Cell, 96:737-49 (1999)).

These techniques allow for the screening of particular populations of cells, such as might be found with hematological malignancies (i.e. minimal residual disease (MRD) in acute leukemic patients) and “non-self” cells in transplantations to prevent Graft-versus-Host Disease (GVHD). Alternatively, these techniques allow for the screening of hematopoietic stem and progenitor cells capable of undergoing proliferation and/or differentiation, as might be found in human umbilical cord blood.

Assays for Antibody Binding

The antibodies of the invention may be assayed for immunospecific binding by any method known in the art. The immunoassays which can be used include but are not limited to competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, which is incorporated by reference herein in its entirety). Exemplary immunoassays are described briefly below (but are not intended by way of limitation).

Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphate at pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate), adding the antibody of interest to the cell lysate, incubating for a period of time (e.g., 1-4 hours) at 4° C., adding protein A and/or protein G sepharose beads to the cell lysate, incubating for about an hour or more at 4° C., washing the beads in lysis buffer and resuspending the beads in SDS/sample buffer. The ability of the antibody of interest to immunoprecipitate a particular antigen can be assessed by, e.g., western blot analysis. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the antibody to an antigen and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads). For further discussion regarding immunoprecipitation protocols see, e.g., Ausubel et al., eds., (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, section 10.16.1.

Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%-20% SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), blocking the membrane with primary antibody (the antibody of interest) diluted in blocking buffer, washing the membrane in washing buffer, blocking the membrane with a secondary antibody (which recognizes the primary antibody, e.g., an anti-human antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g., 32P or 125I) diluted in blocking buffer, washing the membrane in wash buffer, and detecting the presence of the antigen. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected and to reduce the background noise. For further discussion regarding western blot protocols see, e.g., Ausubel et al, eds, (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, section 10.8.1.

ELISAs comprise preparing antigen, coating the well of a 96 well microtiter plate with the antigen, adding the antibody of interest conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the well and incubating for a period of time, and detecting the presence of the antigen. In ELISAs the antibody of interest does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes the antibody of interest) conjugated to a detectable compound may be added to the well. Further, instead of coating the well with the antigen, the antibody may be coated to the well. In this case, a second antibody conjugated to a detectable compound may be added following the addition of the antigen of interest to the coated well. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. For further discussion regarding ELISAs see, e.g., Ausubel et al, eds, (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, section 11.2.1.

The binding affinity of an antibody to an antigen and the off-rate of an antibody-antigen interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g., 3H or 125I) with the antibody of interest in the presence of increasing amounts of unlabeled antigen, and the detection of the antibody bound to the labeled antigen. The affinity of the antibody of interest for a particular antigen and the binding off-rates can be determined from the data by scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays. In this case, the antigen is incubated with antibody of interest conjugated to a labeled compound (e.g., 3H or 125I) in the presence of increasing amounts of an unlabeled second antibody.

Antibodies of the invention may be characterized using immunocytochemisty methods on cells (e.g., mammalian cells, such as CHO cells) transfected with a vector enabling the expression of an antigen or with vector alone using techniques commonly known in the art. Antibodies that bind antigen transfected cells, but not vector-only transfected cells, are antigen specific.

Therapeutic Uses

Table 1D also provides information regarding biological activities and preferred therapeutic uses (i.e. see, “Preferred Indications” column) for polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof). Table 1D also provides information regarding assays which may be used to test polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof) for the corresponding biological activities. The first column (“Gene No.”) provides the gene number in the application for each clone identifier. The second column (“cDNA ATCC Deposit No:Z”) provides the unique clone identifier for each clone as previously described and indicated in Table 1A, Table 1B, and Table 1C. The third column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ ID Number for polypeptide sequences encoded by the corresponding cDNA clones (also as indicated in Table 1A, Table 1B, and Table 2). The fourth column (“Biological Activity”) indicates a biological activity corresponding to the indicated polypeptides (or polynucleotides encoding said polypeptides). The fifth column (“Exemplary Activity Assay”) further describes the corresponding biological activity and also provides information pertaining to the various types of assays which may be performed to test, demonstrate, or quantify the corresponding biological activity.

The present invention is further directed to antibody-based therapies which involve administering antibodies of the invention to an animal, preferably a mammal, and most preferably a human, patient for treating one or more of the disclosed diseases, disorders, or conditions. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (including fragments, analogs and derivatives thereof as described herein) and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein). The antibodies of the invention can be used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate diseases, disorders or conditions associated with aberrant expression and/or activity of a polypeptide of the invention, including, but not limited to, hematopoietic and hematologic diseases and disorders. The treatment and/or prevention of hematopoietic and hematologic diseases and disorders associated with aberrant expression and/or activity of a polypeptide of the invention includes, but is not limited to, alleviating symptoms associated with hematopoietic and hematologic diseases and disorders. Antibodies of the invention may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.

In a specific and preferred embodiment, the present invention is directed to antibody-based therapies which involve administering antibodies of the invention to an animal, preferably a mammal, and most preferably a human, patient for treating hematopoietic and hematologic diseases and disorders. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (e.g., antibodies directed to the full length protein expressed on the cell surface of a mammalian cell; antibodies directed to an epitope of a polypeptide of the invention (such as, for example, a predicted linear epitope shown in Table 1B; or a conformational epitope, including fragments, analogs and derivatives thereof as described herein) and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein). The antibodies of the invention can be used to detect, diagnose, prevent, treat, prognosticate, and/or ameliorate hematopoietic and hematologic diseases, disorders or conditions associated with aberrant expression and/or activity of a polypeptide of the invention. The treatment and/or prevention of hematopoietic and hematologic diseases, disorders or conditions associated with aberrant expression and/or activity of a polypeptide of the invention includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions. Antibodies of the invention may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.

A summary of the ways in which the antibodies of the present invention may be used therapeutically includes binding polynucleotides or polypeptides of the present invention locally or systemically in the body or by direct cytotoxicity of the antibody, e.g. as mediated by complement (CDC) or by effector cells (ADCC). Some of these approaches are described in more detail below. Armed with the teachings provided herein, one of ordinary skill in the art will know how to use the antibodies of the present invention for diagnostic, monitoring or therapeutic purposes without undue experimentation.

The antibodies of this invention may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors (such as, e.g., IL-2, IL-3 and IL-7), for example, which serve to increase the number or activity of effector cells which interact with the antibodies.

The antibodies of the invention may be administered alone or in combination with other types of treatments (e.g., radiation therapy, chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents). Generally, administration of products of a species origin or species reactivity (in the case of antibodies) that is the same species as that of the patient is preferred. Thus, in a preferred embodiment, human antibodies, fragments derivatives, analogs, or nucleic acids, are administered to a human patient for therapy or prophylaxis.

It is preferred to use high affinity and/or potent in vivo inhibiting and/or neutralizing antibodies against polypeptides or polynucleotides of the present invention, fragments or regions thereof, for both immunoassays directed to and therapy of hematopoietic and hematologic diseases or disorders related to polynucleotides or polypeptides, including fragments thereof, of the present invention. Such antibodies, fragments, or regions, will preferably have an affinity for polynucleotides or polypeptides of the invention, including fragments thereof. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10⁻² M, 1×10⁻² M, 5×10⁻³ M, 10⁻³ M, 5×10⁻⁴ M, 10⁻⁴ M, 5×10⁻⁵ M, 10⁻⁵ M, 5×10⁻⁶ M, 10⁻⁶M, 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, 10⁻⁸ M, 5×10⁻⁹ M, 10⁻⁹ M, 5×10⁻¹⁰ M, 10⁻¹⁰ M, 5×10⁻¹¹ M, 10⁻¹¹ M, 5×10⁻¹² M, 10⁻¹² M, 5×10⁻¹³ M, 10⁻¹³ M, 5×10⁻¹⁴ M, 10⁻¹⁴ M, 5×10⁻¹⁵ M, and 10⁻⁵ M.

Gene Therapy

In a specific embodiment, nucleic acids comprising sequences encoding antibodies or functional derivatives thereof, are administered to treat, inhibit or prevent a hematopoietic and hematologic disease or disorder associated with aberrant expression and/or activity of a polypeptide of the invention, by way of gene therapy. Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid. In this embodiment of the invention, the nucleic acids produce their encoded protein that mediates a therapeutic effect.

Any of the methods for gene therapy available in the art can be used according to the present invention. Exemplary methods are described below.

For general reviews of the methods of gene therapy, see Goldspiel et al., Clinical Pharmacy 12:488-505 (1993); Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, TIBTECH 11(5):155-215 (1993). Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); and Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990).

In a preferred embodiment, the compound comprises nucleic acid sequences encoding an antibody, said nucleic acid sequences being part of expression vectors that express the antibody or fragments or chimeric proteins or heavy or light chains thereof in a suitable host. In particular, such nucleic acid sequences have promoters operably linked to the antibody coding region, said promoter being inducible or constitutive, and, optionally, tissue-specific. In another particular embodiment, nucleic acid molecules are used in which the antibody coding sequences and any other desired sequences are flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intrachromosomal expression of the antibody encoding nucleic acids (Koller and Smithies, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature 342:435-438 (1989). In specific embodiments, the expressed antibody molecule is a single chain antibody; alternatively, the nucleic acid sequences include sequences encoding both the heavy and light chains, or fragments thereof, of the antibody.

Delivery of the nucleic acids into a patient may be either direct, in which case the patient is directly exposed to the nucleic acid or nucleic acid-carrying vectors, or indirect, in which case, cells are first transformed with the nucleic acids in vitro, then transplanted into the patient. These two approaches are known, respectively, as in vivo or ex vivo gene therapy.

In a specific embodiment, the nucleic acid sequences are directly administered in vivo, where it is expressed to produce the encoded product. This can be accomplished by any of numerous methods known in the art, e.g., by constructing them as part of an appropriate nucleic acid expression vector and administering it so that they become intracellular, e.g., by infection using defective or attenuated retrovirals or other viral vectors (see U.S. Pat. No. 4,980,286), or by direct injection of naked DNA, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, encapsulation in liposomes, microparticles, or microcapsules, or by administering them in linkage to a peptide which is known to enter the nucleus, by administering it in linkage to a ligand subject to receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)) (which can be used to target cell types specifically expressing the receptors), etc. In another embodiment, nucleic acid-ligand complexes can be formed in which the ligand comprises a fusogenic viral peptide to disrupt endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (see, e.g., PCT Publications WO 92/06180; WO 92/22635; WO92/20316; WO93/14188, WO 93/20221). Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature 342:435-438 (1989)).

In a specific embodiment, viral vectors that contain nucleic acid sequences encoding an antibody of the invention are used. For example, a retroviral vector can be used (see Miller et al., Meth. Enzymol. 217:581-599 (1993)). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. The nucleic acid sequences encoding the antibody to be used in gene therapy are cloned into one or more vectors, which facilitates delivery of tihe gene into a patient. More detail about retroviral vectors can be found in Boesen et al., Biotherapy 6:291-302 (1994), which describes the use of a retroviral vector to deliver the mdr1 gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., J. Clin. Invest. 93:644-651 (1994); Kiem et al., Blood 83:1467-1473 (1994); Salmons and Gunzberg, Human Gene Therapy 4:129-141 (1993); and Grossman and Wilson, Curr. Opin. in Genetics and Devel. 3:110-114 (1993).

Adenoviruses are other viral vectors that can be used in gene therapy. Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, Current Opinion in Genetics and Development 3:499-503 (1993) present a review of adenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10 (1994) demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1992); Mastrangeli et al., J. Clin. Invest 91:225-234 (1993); PCT Publication WO94/12649; and Wang, et al., Gene Therapy 2:775-783 (1995). In a preferred embodiment, adenovirus vectors are used.

Adeno-associated virus (AAV) has also been proposed for use in gene therapy (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993); U.S. Pat. No. 5,436,146).

Another approach to gene therapy involves transferring a gene to cells in tissue culture by such methods as electroporation, lipofection, calcium phosphate mediated transfection, or viral infection. Usually, the method of transfer includes the transfer of a selectable marker to the cells. The cells are then placed under selection to isolate those cells that have taken up and are expressing the transferred gene. Those cells are then delivered to a patient.

In this embodiment, the nucleic acid is introduced into a cell prior to administration in vivo of the resulting recombinant cell. Such introduction can be carried out by any method known in the art, including but not limited to transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, spheroplast fusion, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see, e.g., Loeffler and Behr, Meth. Enzymol. 217:599-618 (1993); Cohen et al., Meth. Enzymol. 217:618-644 (1993); Cline, Pharmac. Ther. 29:69-92m (1985) and may be used in accordance with the present invention, provided that the necessary developmental and physiological functions of the recipient cells are not disrupted. The technique should provide for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and preferably heritable and expressible by its cell progeny.

The resulting recombinant cells can be delivered to a patient by various methods known in the art. Recombinant blood cells (e.g., hematopoietic stem or progenitor cells) are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, patient state, etc., and can be determined by one skilled in the art.

Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood, fetal liver, etc.

In a preferred embodiment, the cell used for gene therapy is autologous to the patient.

In an embodiment in which recombinant cells are used in gene therapy, nucleic acid sequences encoding an antibody are introduced into the cells such that they are expressible by the cells or their progeny, and the recombinant cells are then administered in vivo for therapeutic effect. In a specific embodiment, stem or progenitor cells are used. Any stem and/or progenitor cells which can be isolated and maintained in vitro can potentially be used in accordance with this embodiment of the present invention (see e.g. PCT Publication WO 94/08598; Stemple and Anderson, Cell 71:973-985 (1992); Rheinwald, Meth. Cell Bio. 21A:229 (1980); and Pittelkow and Scott, Mayo Clinic Proc. 61:771 (1986)).

In a specific embodiment, the nucleic acid to be introduced for purposes of gene therapy comprises an inducible promoter operably linked to the coding region, such that expression of the nucleic acid is controllable by the presence or absence of an appropriate inducer of transcription.

Demonstration of Therapeutic or Prophylactic Activity

The compounds or pharmaceutical compositions of the invention are preferably tested in vitro, and then in vivo for the desired therapeutic or prophylactic activity, prior to use in humans. For example, in vitro assays to demonstrate the therapeutic or prophylactic utility of a compound or pharmaceutical composition include, the effect of a compound on a cell line or a patient tissue sample. The effect of the compound or composition on the cell line and/or tissue sample can be determined utilizing techniques known to those of skill in the art including, but not limited to, rosette formation assays and cell lysis assays. In accordance with the invention, in vitro assays which can be used to determine whether administration of a specific compound is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a compound, and the effect of such compound upon the tissue sample is observed.

Therapeutic/Prophylactic Administration and Composition

The invention provides methods of treatment, inhibition and prophylaxis by administration to a subject of an effective amount of a compound or pharmaceutical composition of the invention, preferably a polypeptide or antibody of the invention. In a preferred embodiment, the compound is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects). The subject is preferably an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human.

Formulations and methods of administration that can be employed when the compound comprises a nucleic acid or an immunoglobulin are described above; additional appropriate formulations and routes of administration can be selected from among those described herein below.

Various delivery systems are known and can be used to administer a compound of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compounds or compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.

In a specific embodiment, it may be desirable to administer the pharmaceutical compounds or compositions of the invention locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Preferably, when administering a protein, including an antibody, of the invention, care must be taken to use materials to which the protein does not absorb.

In another embodiment, the compound or composition can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.)

In yet another embodiment, the compound or composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, e.g., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).

Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).

In a specific embodiment where the compound of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al., Proc. Natl. Acad. Sci. USA 88:1864-1868 (1991)), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.

The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a compound, and a pharmaceutically acceptable carrier. In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and mor particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

The compounds of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

The amount of the compound of the invention which will be effective in the treatment, inhibition and prevention of a disease or disorder associated with aberrant expression and/or activity of a polypeptide of the invention can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

For antibodies, the dosage administered to a patient is typically 0.1 mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosage administered to a patient is between 0.1 mg/kg and 20 mg/kg of the patient's body weight, more preferably 1 mg/kg to 10 mg/kg of the patient's body weight. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies of the invention may be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation.

The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

Diagnosis and Imaging

Labeled antibodies, and derivatives and analogs thereof, which specifically bind to a polypeptide of interest can be used for diagnostic purposes to detect, diagnose, prognosticate, or monitor hematopoietic and hematologic diseases, disorders, and/or conditions associated with the aberrant expression and/or activity of a polypeptide of the invention. The invention provides for the detection of aberrant expression of a polypeptide of interest, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of aberrant expression.

The invention provides a diagnostic assay for diagnosing a hematopoietic and hematologic disease or disorder, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of a particular hematopoietic and hematologic disease or disorder. With respect to hematopoietic cancers, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the hematopoietic cancer.

Antibodies of the invention can be used to assay protein levels in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen et al., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (125I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (112In), and technetium (99Tc); luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.

One facet of the invention is the detection and diagnosis of a disease or disorder associated with aberrant expression of a polypeptide of interest in an animal, preferably a mammal and most preferably a human. In one embodiment, diagnosis comprises: a) administering (for example, parenterally, subcutaneously, or intraperitoneally) to a subject an effective amount of a labeled molecule which specifically binds to the polypeptide of interest; b) waiting for a time interval following the administering for permitting the labeled molecule to preferentially concentrate at sites in the subject where the polypeptide is expressed (and for unbound labeled molecule to be cleared to background level); c) determining background level; and d) detecting the labeled molecule in the subject, such that detection of labeled molecule above the background level indicates that the subject has a particular disease or disorder associated with aberrant expression of the polypeptide of interest. Background level can be determined by various methods including, comparing the amount of labeled molecule detected to a standard value previously determined for a particular system.

It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 milicuries of 99mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the specific protein. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments.” (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).

Depending on several variables, including the type of label used and the mode of administration, the time interval following the administration for permitting the labeled molecule to preferentially concentrate at sites in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. In another embodiment the time interval following administration is 5 to 20 days or 5 to 10 days.

In an embodiment, monitoring of the disease or disorder is carried out by repeating the method for diagnosing the disease or disease, for example, one month after initial diagnosis, six months after initial diagnosis, one year after initial diagnosis, etc.

Presence of the labeled molecule can be detected in the patient using methods known in the art for in vivo scanning. These methods depend upon the type of label used. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used in the diagnostic methods of the invention include, but are not limited to, computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance imaging (MRI), and sonography.

In a specific embodiment, the molecule is labeled with a radioisotope and is detected in the patient using a radiation responsive surgical instrument (Thurston et al., U.S. Pat. No. 5,441,050). In another embodiment, the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument. In another embodiment, the molecule is labeled with a positron emitting metal and is detected in the patent using positron emission-tomography. In yet another embodiment, the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).

Kits

The present invention provides kits that can be used in the above methods. In one embodiment, a kit comprises an antibody of the invention, preferably a purified antibody, in one or more containers. In a specific embodiment, the kits of the present invention contain a substantially isolated polypeptide comprising an epitope which is specifically immunoreactive with an antibody included in the kit. Preferably, the kits of the present invention further comprise a control antibody which does not react with the polypeptide of interest. In another specific embodiment, the kits of the present invention contain a means for detecting the binding of an antibody to a polypeptide of interest (e.g., the antibody may be conjugated to a detectable substrate such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second antibody which recognizes the first antibody may be conjugated to a detectable substrate).

In another specific embodiment of the present invention, the kit is a diagnostic kit for use in screening serum containing antibodies specific against proliferative and/or cancerous polynucleotides and polypeptides. Such a kit may include a control antibody that does not react with the polypeptide of interest. Such a kit may include a substantially isolated polypeptide antigen comprising an epitope which is specifically immunoreactive with at least one anti-polypeptide antigen antibody. Further, such a kit includes means for detecting the binding of said antibody to the antigen (e.g., the antibody may be conjugated to a fluorescent compound such as fluorescein or rhodamine which can be detected by flow cytometry). In specific embodiments, the kit may include a recombinantly produced or chemically synthesized polypeptide antigen. The polypeptide antigen of the kit may also be attached to a solid support.

In a more specific embodiment the detecting means of the above-described kit includes a solid support to which said polypeptide antigen is attached. Such a kit may also include a non-attached reporter-labeled anti-human antibody. In this embodiment, binding of the antibody to the polypeptide antigen can be detected by binding of the said reporter-labeled antibody.

In an additional embodiment, the invention includes a diagnostic kit for use in screening serum containing antigens of the polypeptide of the invention. The diagnostic kit includes a substantially isolated antibody specifically immunoreactive with polypeptide or polynucleotide antigens, and means for detecting the binding of the polynucleotide or polypeptide antigen to the antibody. In one embodiment, the antibody is attached to a solid support. In a specific embodiment, the antibody may be a monoclonal antibody. The detecting means of the kit may include a second, labeled monoclonal antibody. Alternatively, or in addition, the detecting means may include a labeled, competing antigen.

In one diagnostic configuration, test serum is reacted with a solid phase reagent having a surface-bound antigen obtained by the methods of the present invention. After binding with specific antigen antibody to the reagent and removing unbound serum components by washing, the reagent is reacted with reporter-labeled anti-human antibody to bind reporter to the reagent in proportion to the amount of bound anti-antigen antibody on the solid support. The reagent is again washed to remove unbound labeled antibody, and the amount of reporter associated with the reagent is determined. Typically, the reporter is an enzyme which is detected by incubating the solid phase in the presence of a suitable fluorometric, luminescent or colorimetric substrate (Sigma, St. Louis, Mo.).

The solid surface reagent in the above assay is prepared by known techniques for attaching protein material to solid support material, such as polymeric beads, dip sticks, 96-well plate or filter material. These attachment methods generally include non-specific adsorption of the protein to the support or covalent attachment of the protein, typically through a free amine group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group. Alternatively, streptavidin coated plates can be used in conjunction with biotinylated antigen(s).

Thus, the invention provides an assay system or kit for carrying out this diagnostic method. The kit generally includes a support with surface-bound recombinant antigens, and a reporter-labeled anti-human antibody for detecting surface-bound anti-antigen antibody.

Uses of the Polynucleotides

Each of the polynucleotides identified herein can be used in numerous ways as reagents. The following description should be considered exemplary and utilizes known techniques.

The polynucleotides of the present invention are useful for chromosome identification. There exists an ongoing need to identify new chromosome markers, since few chromosome marking reagents, based on actual sequence data (repeat polymorphisms), are presently available. Each sequence is specifically targeted to and can hybridize with a particular location on an individual human chromosome, thus each polynucleotide of the present invention can routinely be used as a chromosome marker using techniques known in the art. Table 1B. 1, column 8 provides the chromosome location of some of the polynucleotides of the invention.

Briefly, sequences can be mapped to chromosomes by preparing PCR primers (preferably at least 15 bp (e.g., 15-25 bp) from the sequences shown in SEQ ID NO:X. Primers can optionally be selected using computer analysis so that primers do not span more than one predicted exon in the genomic DNA. These primers are then used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to SEQ ID NO:X will yield an amplified fragment.

Similarly, somatic hybrids provide a rapid method of PCR mapping the polynucleotides to particular chromosomes. Three or more clones can be assigned per day using a single thermal cycler. Moreover, sublocalization of the polynucleotides can be achieved with panels of specific chromosome fragments. Other gene mapping strategies that can be used include in situ hybridization, prescreening with labeled flow-sorted chromosomes, preselection by hybridization to construct chromosome specific-cDNA libraries, and computer mapping techniques (See, e.g., Shuler, Trends Biotechnol 16:456-459 (1998) which is hereby incorporated by reference in its entirety).

Precise chromosomal location of the polynucleotides can also be achieved using fluorescence in situ hybridization (FISH) of a metaphase chromosomal spread. This technique uses polynucleotides as short as 500 or 600 bases; however, polynucleotides 2,000 bp are preferred. For a review of this technique, see Verma et al., “Human Chromosomes: a Manual of Basic Techniques,” Pergamon Press, New York (1988).

For chromosome mapping, the polynucleotides can be used individually (to mark a: single chromosome or a single site on that chromosome) or in panels (for marking multiple sites and/or multiple chromosomes).

Thus, the present invention also provides a method for chromosomal localization which involves (a) preparing PCR primers from the polynucleotide sequences in Table 1B and/or Table 2 and SEQ ID NO:X and (b) screening somatic cell hybrids containing individual chromosomes.

The polynucleotides of the present invention would likewise be useful for radiation hybrid mapping, HAPPY mapping, and long range restriction mapping. For a review of these techniques and others known in the art, see, e.g. Dear, “Genome Mapping: A Practical Approach,” IRL Press at Oxford University Press, London (1997); Aydin, J. Mol. Med. 77:691-694 (1999); Hacia et al., Mol. Psychiatry 3:483-492 (1998); Herrick et al., Chromosome Res. 7:409-423 (1999); Hamilton et al., Methods Cell Biol. 62:265-280 (2000); and/or Ott, J. Hered. 90:68-70 (1999) each of which is hereby incorporated by reference in its entirety.

Once a polynucleotide has been mapped to a precise chromosomal location, the physical position of the polynucleotide can be used in linkage analysis. Linkage analysis establishes coinheritance between a chromosomal location and presentation of a particular disease. (Disease mapping data are found, for example, in V. McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library)). Column 9 of Table 1B.1 provides an OMIM reference identification number of diseases associated with the cytologic band disclosed in column 8 of Table 1B.1, as determined using techniques described herein and by reference to Table 5. Assuming 1 megabase mapping resolution and one gene per 20 kb, a cDNA precisely localized to a chromosomal region associated with the disease could be one of 50-500 potential causative genes.

Thus, once coinheritance is established, differences in a polynucleotide of the invention and the corresponding gene between affected and unaffected individuals can be examined. First, visible structural alterations in the chromosomes, such as deletions or translocations, are examined in chromosome spreads or by PCR. If no structural alterations exist, the presence of point mutations are ascertained. Mutations observed in some or all affected individuals, but not in normal individuals, indicates that the mutation may cause the disease. However, complete sequencing of the polypeptide and the corresponding gene from several normal individuals is required to distinguish the mutation from a polymorphism. If a new polymorphism is identified, this polymorphic polypeptide can be used for further linkage analysis.

Furthermore, increased or decreased expression of the gene in affected individuals as compared to unaffected individuals can be assessed using the polynucleotides of the invention. Any of these alterations (altered expression, chromosomal rearrangement, or mutation) can be used as a diagnostic or prognostic marker. Diagnostic and prognostic methods, kits and reagents encompassed by the present invention are briefly described below and more thoroughly elsewhere herein (see e.g., the sections labeled “Antibodies”, “Diagnostic Assays”, and “Methods for Detecting Diseases”).

Thus, the invention also provides a diagnostic method useful during diagnosis of a disorder, involving measuring the expression level of polynucleotides of the present invention in cells or body fluid from an individual and comparing the measured gene expression level with a standard level of polynucleotide expression level, whereby an increase or decrease in the gene expression level compared to the standard is indicative of a disorder. Additional non-limiting examples of diagnostic methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., Example 12).

In still another embodiment, the invention includes a kit for analyzing samples for the presence of proliferative and/or cancerous polynucleotides derived from a test subject. In a general embodiment, the kit includes at least one polynucleotide probe containing a nucleotide sequence that will specifically hybridize with a polynucleotide of the invention and a suitable container. In a specific embodiment, the kit includes two polynucleotide probes defining an internal region of the polynucleotide of the invention, where each probe has one strand containing a 31′mer-end internal to the region. In a further embodiment, the probes may be useful as primers for polymerase chain reaction amplification.

Where a diagnosis of a related disorder, including, for example, diagnosis of a tumor, has already been made according to conventional methods, the present invention is useful as a prognostic indicator, whereby patients exhibiting enhanced or depressed polynucleotide of the invention expression will experience a worse clinical outcome relative to patients expressing the gene at a level nearer the standard level.

By “measuring the expression level of polynucleotides of the invention” is intended qualitatively or quantitatively measuring or estimating the level of the polypeptide of the invention or the level of the mRNA encoding the polypeptide of the invention in a first biological sample either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing to the polypeptide level or mRNA level in a second biological sample). Preferably, the polypeptide level or mRNA level in the first biological sample is measured or estimated and compared to a standard polypeptide level or mRNA level, the standard being taken from a second biological sample obtained from an individual not having the related disorder or being determined by averaging levels from a population of individuals not having a related disorder. As will be appreciated in the art, once a standard polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.

By “biological sample” is intended any biological sample obtained from an individual, body fluid, cell line, tissue culture, or other source which contains polypeptide of the present invention or the corresponding mRNA. As indicated, biological samples include body fluids (such as semen, lymph, vaginal pool, sera, plasma, urine, synovial fluid and spinal fluid) which contain the polypeptide of the present invention, and tissue sources found to express the polypeptide of the present invention. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art. Where the biological sample is to include mRNA, a tissue biopsy is the preferred source.

The method(s) provided above may preferably be applied in a diagnostic method and/or kits in which polynucleotides and/or polypeptides of the invention are attached to a solid support. In one exemplary method, the support may be a “gene chip” or a “biological chip” as described in U.S. Pat. Nos. 5,837,832, 5,874,219, and 5,856,174. Further, such a gene chip with polynucleotides of the invention attached may be used to identify polymorphisms between the isolated polynucleotide sequences of the invention, with polynucleotides isolated from a test subject. The knowledge of such polymorphisms (i.e. their location, as well as, their existence) would be beneficial in identifying disease loci for many disorders, such as for example, in neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, digestive disorders, metabolic disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions. Such a method is described in U.S. Pat. Nos. 5,858,659 and 5,856,104. The U.S. Patents referenced supra are hereby incorporated by reference in their entirety herein.

The present invention encompasses polynucleotides of the present invention that are chemically synthesized, or reproduced as peptide nucleic acids (PNA), or according to other methods known in the art. The use of PNAs would serve as the preferred form if the polynucleotides of the invention are incorporated onto a solid support, or gene chip. For the purposes of the present invention, a peptide nucleic acid (PNA) is a polyamide type of DNA analog and the monomeric units for adenine, guanine, thymine and cytosine are available commercially (Perceptive Biosystems). Certain components of DNA, such as phosphorus, phosphorus oxides, or deoxyribose derivatives, are not present in PNAs. As disclosed by Nielsen et al., Science 254, 1497 (1991); and Egholm et al., Nature 365, 666 (1993), PNAs bind specifically and tightly to complementary DNA strands and are not degraded by nucleases. In fact, PNA binds more strongly to DNA than DNA itself does. This is probably because there is no electrostatic repulsion between the two strands, and also the polyamide backbone is more flexible. Because of this, PNA/DNA duplexes bind under a wider range of stringency conditions than DNA/DNA duplexes, making it easier to perform multiplex hybridization. Smaller probes can be used than with DNA due to the strong binding. In addition, it is more likely that single base mismatches can be determined with PNA/DNA hybridization because a single mismatch in a PNA/DNA 15-mer lowers the melting point (T.sub.m) by 8°-20° C., vs. 4°-16° C. for the DNA/DNA 15-mer duplex. Also, the absence of charge groups in PNA means that hybridization can be done at low ionic strengths and reduce possible interference by salt during the analysis.

The compounds of the present invention have uses which include, but are not limited to, detecting cancer in mammals. In particular the invention is useful during diagnosis of pathological cell proliferative neoplasias which include, but are not limited to: acute myelogenous leukemias including acute monocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute erythroleukemia, acute megakaryocytic leukemia, and acute undifferentiated leukemia, etc.; and chronic myelogenous leukemias including chronic myelomonocytic leukemia, chronic granulocytic leukemia, etc. Preferred mammals include monkeys, apes, cats, dogs, cows, pigs, horses, rabbits and humans. Particularly preferred are humans.

Pathological cell proliferative disorders are often associated with inappropriate activation of proto-oncogeres. (Gelma n, E. P. et al., “The Etiology of Acute Leukemia: Molecular Genetics and Viral Oncology,” in Neoplastic Diseases of the Blood, Vol 1., Wiernik, P. H. et al. eds., 161-182 (1985)). Neoplasias are now believed to result from the qualitative alteration of a normal cellular gene product, or from the quantitative modification of gene expression by insertion into the chromosome of a viral sequence, by chromosomal translocation of a gene to a more actively transcribed region, or by some other mechanism. (Gelmann et al., supra) It is likely that mutated or altered expression of specific genes is involved in the pathogenesis of some leukemias, among other tissues and cell types. (Gelmann et al., supra) Indeed, the human counterparts of the oncogenes involved in some animal neoplasias have been amplified or translocated in some cases of human leukemia and carcinoma. (Gelmann et al., supra)

For example, c-myc expression is highly amplified in the non-lymphocytic leukemia cell line HL-60. When HL-60 cells are chemically induced to stop proliferation, the level of c-myc is found to be downregulated. (International Publication Number WO 91/15580). However, it has been shown that exposure of HL-60 cells to a DNA construct that is complementary to the 5′ end of c-myc or c-myb blocks translation of the corresponding mRNAs which down-regulates expression of the c-myc or c-myb proteins and causes arrest of cell proliferation and differentiation of the treated cells. (International Publication Number WO 91/15580; Wickstrom et al., Proc. Natl. Acad. Sci. 85:1028 (1988); Anfossi et al., Proc. Natl. Acad. Sci. 86:3379 (1989)). However, the skilled artisan would appreciate the present invention's usefulness is not be limited to treatment, prevention, and/or prognosis of proliferative disorders of cells and tissues of hematopoietic origin, in light of the numerous cells and cell types of varying origins which are known to exhibit proliferative phenotypes.

In addition to the foregoing, a polynucleotide of the present invention can be used to control gene expression through triple helix formation or through antisense DNA or RNA. Antisense techniques are discussed, for example, in Okano, J. Neurochem. 56: 560 (1991); “Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Triple helix formation is discussed in, for instance Lee et al., Nucleic Acids Research 6: 3073 (1979); Cooney et al., Science 241: 456 (1988); and Dervan et al., Science 251: 1360 (1991). Both methods rely on binding of the polynucleotide to a complementary DNA or RNA For these techniques, preferred polynucleotides are usually oligonucleotides 20 to 40 bases in length and complementary to either the region of the gene involved in transcription (triple helix—see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J. Neurochem. 56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helix formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. The oligonucleotide described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of polypeptide of the present invention antigens. Both techniques are effective in model systems, and the information disclosed herein can be used to design antisense or triple helix polynucleotides in an effort to treat disease, and in particular, for the treatment of proliferative diseases and/or conditions. Non-limiting antisense and triple helix methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., the section labeled “Antisense and Ribozyme (Antagonists)”).

Polynucleotides of the present invention are also useful in gene therapy. One goal of gene therapy is to insert a normal gene into an organism having a defective gene, in an effort to correct the genetic defect. The polynucleotides disclosed in the present invention offer a means of targeting such genetic defects in a highly accurate manner. Another goal is to insert a new gene that was not present in the host genome, thereby producing a new trait in the host cell. Additional non-limiting examples of gene therapy methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., the sections labeled “Gene Therapy Methods”, and Examples 16, 17 and 18).

The polynucleotides are also useful for identifying individuals from minute biological samples. The United States military, for example, is considering the use of restriction fragment length polymorphism (RFLP) for identification of its personnel. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identifying personnel. This method does not suffer from the current limitations of “Dog Tags” which can be lost, switched, or stolen, making positive identification difficult. The polynucleotides of the present invention can be used as additional DNA markers for RFLP.

The polynucleotides of the present invention can also be used as an alternative to RFLP, by determining the actual base-by-base DNA sequence of selected portions of an individual's genome. These sequences can be used to prepare PCR primers for amplifying and isolating such selected DNA, which can then be sequenced. Using this technique, individuals can be identified because each individual will have a unique set of DNA sequences. Once a unique ID database is established for an individual, positive identification of that individual, living or dead, can be made from extremely small tissue samples.

Forensic biology also benefits from using DNA-based identification techniques as disclosed herein. DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, semen, synovial fluid, amniotic fluid, breast milk, lymph, pulmonary sputum or surfactant, urine, fecal matter, etc., can be amplified using PCR. In one prior art technique, gene sequences amplified from polymorphic loci, such as DQa class II HLA gene, are used in forensic biology to identify individuals. (Erlich, H., PCR Technology, Freeman and Co. (1992)). Once these specific polymorphic loci are amplified, they are digested with one or more restriction enzymes, yielding an identifying set of bands on a Southern blot probed with DNA corresponding to the DQa class II HLA gene. Similarly, polynucleotides of the present invention can be used as polymorphic markers for forensic purposes.

There is also a need for reagents capable of identifying the source of a particular tissue. Such need arises, for example, in forensics when presented with tissue of unknown origin. Appropriate reagents can comprise, for example, DNA probes or primers prepared from the sequences of the present invention, specific to tissues, including but not limited to those shown in Table 1B. Panels of such reagents can identify tissue by species and/or by organ type. In a similar fashion, these reagents can be used to screen tissue cultures for contamination. Additional non-limiting examples of such uses are further described herein.

The polynucleotides of the present invention are also useful as hybridization probes for differential identification of the tissue(s) or cell type(s) present in a biological sample. Similarly, polypeptides and antibodies directed to polypeptides of the present invention are useful to provide immunological probes for differential identification of the tissue(s) (e.g., immunohistochemistry assays) or cell type(s) (e.g., immunocytochemistry assays). In addition, for a number of disorders of the above tissues or cells, significantly higher or lower levels of gene expression of the polynucleotides/polypeptides of the present invention may be detected in certain tissues (e.g., tissues expressing polypeptides and/or polynucleotides of the present invention, for example, those disclosed in column 5 of Table 1B.2, and/or cancerous and/or wounded tissues) or bodily fluids (e.g., semen, lymph, vaginal pool, serum, plasma, urine, synovial fluid or spinal fluid) taken from an individual having such a disorder, relative to a “standard” gene expression level, i.e., the expression level in healthy tissue from an individual not having the disorder.

Thus, the invention provides a diagnostic method of a disorder, which involves: (a) assaying gene expression level in cells or body fluid of an individual; (b) comparing the gene expression level with a standard gene expression level, whereby an increase or decrease in the assayed gene expression level compared to the standard expression level is indicative of a disorder.

In the very least, the polynucleotides of the present invention can be used as molecular weight markers on Southern gels, as diagnostic probes for the presence of a specific mRNA in a particular cell type, as a probe to “subtract-out” known sequences in the process of discovering novel polynucleotides, for selecting and making oligomers for attachment to a “gene chip” or other support, to raise anti-DNA antibodies using DNA immunization techniques, and as an antigen to elicit an immune response.

Uses of the Polypeptides

Each of the polypeptides identified herein can be used in numerous ways. The following description should be considered exemplary and utilizes known techniques.

Polypeptides and antibodies directed to polypeptides of the present invention are useful to provide immunological probes for differential identification of the tissue(s) (e.g., immunohistochemistry assays such as, for example, ABC immunoperoxidase (Hsu et al., J. Histochem. Cytochem. 29:577-580 (1981)) or cell type(s) (e.g., immunocytochemistry assays).

Antibodies can be used to assay levels of polypeptides encoded by polynucleotides of the invention in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalcanen, et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, et al., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (¹³¹I, ¹²⁵I, ¹²³I, ¹²¹I), carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium (^(115m)In, ^(113m)In, ¹¹²In, ¹¹¹In), and technetium (⁹⁹Tc, ^(99m)Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga), palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F), ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, ⁹⁷Ru; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.

In addition to assaying levels of polypeptide of the present invention in a biological sample, proteins can also be detected in vivo by imaging. Antibody labels or markers for in vivo imaging of protein include those detectable by X-radiography, NMR or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma.

A protein-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example, ¹³¹I, ¹¹²In, ^(99m)TC, (¹³¹I, ¹²⁵I, ¹²³I, ¹²¹I), carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium (^(115m)In, ^(113m)In, ¹¹²In, ¹¹¹In), and technetium (⁹⁹Tc, ^(99m)Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga), palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F, ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, ⁹⁷Ru), a radio-opaque substance, or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously or intraperitoneally) into the mammal to be examined for immune system disorder. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of ^(99m)Tc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which express the polypeptide encoded by a polynucleotide of the invention. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments” (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).

In one embodiment, the invention provides a method for the specific delivery of compositions of the invention to cells by administering polypeptides of the invention (e.g., polypeptides encoded by polynucleotides of the invention and/or antibodies) that are associated with heterologous polypeptides or nucleic acids. In one example, the invention provides a method for delivering a therapeutic protein into the targeted cell. In another example, the invention provides a method for delivering a single stranded nucleic acid (e.g., antisense or ribozymes) or double stranded nucleic acid (e.g., DNA that can integrate into the cell's genome or replicate episomally and that can be transcribed) into the targeted cell.

In another embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention in association with toxins or cytotoxic prodrugs.

By “toxin” is meant one or more compounds that bind and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell's death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. “Toxin” also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, ²¹³Bi, or other radioisotopes such as, for example, ¹⁰³Pd, ¹³³Xe, ¹³¹I, ⁶⁸Ge, ⁵⁷Co, ⁶⁵Zn, ⁸⁵Sr, ³²P, ³⁵S, ⁹⁰Y, ¹⁵³Sm, ¹⁵³Gd, ¹⁶⁹Yb, ⁵¹Cr, ⁵⁴Mn, ⁷⁵Se, ¹¹³Sn, ⁹⁰Yttrium, ¹¹⁷Tin, ¹⁸⁶Rhenium, ¹⁶⁶Holmium, and ¹⁸⁸Rhenium; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin. In a specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope ⁹⁰Y. In another specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope ¹¹¹In. In a further specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope ¹³¹I.

Techniques known in the art may be applied to label polypeptides of the invention (including antibodies). Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see e.g., U.S. Pat. Nos. 5,756,065; 5,714,631; 5,696,239; 5,652,361; 5,505,931; 5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560; and 5,808,003; the contents of each of which are hereby incorporated by reference in its entirety).

Thus, the invention provides a diagnostic method of a disorder, which involves (a) assaying the expression level of a polypeptide of the present invention in cells or body fluid of an individual; and (b) comparing the assayed polypeptide expression level with a standard polypeptide expression level, whereby an increase or decrease in the assayed polypeptide expression level compared to the standard expression level is indicative of a disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.

Moreover, polypeptides of the present invention can be used to treat or prevent diseases or conditions such as, for example, neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions. For example, patients can be administered a polypeptide of the present invention in an effort to replace absent or decreased levels of the polypeptide (e.g., insulin), to supplement absent or decreased levels of a different polypeptide (e.g., hemoglobin S for hemoglobin B, SOD, catalase, DNA repair proteins), to inhibit the activity of a polypeptide (e.g., an oncogene or tumor supressor), to activate the activity of a polypeptide (e.g., by binding to a receptor), to reduce the activity of a membrane bound receptor by competing with it for free ligand (e.g., soluble TNP receptors used in reducing inflammation), or to bring about a desired response (e.g., blood vessel growth inhibition, enhancement of the immune response to proliferative cells or tissues).

Similarly, antibodies directed to a polypeptide of the present invention can also be used to treat disease (as described supra, and elsewhere herein). For example, administration of an antibody directed to a polypeptide of the present invention can bind, and/or neutralize the polypeptide, and/or reduce overproduction of the polypeptide. Similarly, administration of an antibody can activate the polypeptide, such as by binding to a polypeptide bound to a membrane (receptor).

At the very least, the polypeptides of the present invention can be used as molecular weight markers on SDS-PAGE gels or on molecular sieve gel filtration columns using methods well known to those of skill in the art. Polypeptides can also be used to raise antibodies, which in turn are used to measure protein expression from a recombinant cell, as a way of assessing transformation of the host cell. Moreover, the polypeptides of the present invention can be used to test the biological activities described herein.

Diagnostic Assays

The compounds of the present invention are useful for diagnosis, treatment, prevention and/or prognosis of various disorders in mammals, preferably humans. Such disorders include, but are not limited to, those related to biological activities described in Table 1D and, also as described herein under the section heading “biological Activities”.

For a number of disorders, substantially altered (increased or decreased) levels of gene expression can be detected in tissues, cells or bodily fluids (e.g., sera, plasma, urine, semen, synovial fluid or spinal fluid) taken from an individual having such a disorder, relative to a “standard” gene expression level, that is, the expression level in tissues or bodily fluids from an individual not having the disorder. Thus, the invention provides a diagnostic method useful during diagnosis of a disorder, which involves measuring the expression level of the gene encoding the polypeptide in tissues, cells or body fluid from an individual and comparing the measured gene expression level with a standard gene expression level, whereby an increase or decrease in the gene expression level(s) compared to the standard is indicative of a disorder. These diagnostic assays may be performed in vivo or in vitro, such as, for example, on blood samples, biopsy tissue or autopsy tissue.

The present invention is also useful as a prognostic indicator, whereby patients exhibiting enhanced or depressed gene expression will experience a worse clinical outcome relative to patients expressing the gene at a level nearer the standard level.

In certain embodiments, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose and/or prognosticate diseases and/or disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1B.2, column 5 (Tissue Distribution Library Code).

By “assaying the expression level of the gene encoding the polypeptide” is intended qualitatively or quantitatively measuring or estimating the level of the polypeptide of the invention or the level of the mRNA encoding the polypeptide of the invention in a first biological sample either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing to the polypeptide level or mRNA level in a second biological sample). Preferably, the polypeptide expression level or mRNA level in the first biological sample is measured or estimated and compared to a standard polypeptide level or mRNA level, the standard being taken from a second biological sample obtained from an individual not having the disorder or being determined by averaging levels from a population of individuals not having the disorder. As will be appreciated in the art, once a standard polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.

By “biological sample” is intended any biological sample obtained from an individual, cell line, tissue culture, or other source containing polypeptides of the invention (including portions thereof) or mRNA. As indicated, biological samples include body fluids (such as sera, plasma, urine, synovial fluid and spinal fluid) and tissue sources found to express the full length or fragments thereof of a polypeptide or mRNA. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art. Where the biological sample is to include mRNA, a tissue biopsy is the preferred source.

Total cellular RNA can be isolated from a biological sample using any suitable technique such as the single-step guanidinium-thiocyanate-phenol-chloroform method described in Chomczynski and Sacchi, Anal. Biochem. 162:156-159 (1987). Levels of mRNA encoding the polypeptides of the invention are then assayed using any appropriate method. These include Northern blot analysis, S1 nuclease mapping, the polymerase chain reaction (PCR), reverse transcription in combination with the polymerase chain reaction (RT-PCR), and reverse transcription in combination with the ligase chain reaction (RT-LCR).

The present invention also relates to diagnostic assays such as quantitative and diagnostic assays for detecting levels of polypeptides of the invention, in a biological sample (e.g., cells and tissues), including determination of normal and abnormal levels of polypeptides. Thus, for instance, a diagnostic assay in accordance with the invention for detecting over-expression of polypeptides of the invention compared to normal control tissue samples may be used to detect the presence of tumors. Assay techniques that can be used to determine levels of a polypeptide, such as a polypeptide of the present invention in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays. Assaying polypeptide levels in a biological sample can occur using any art-known method.

Assaying polypeptide levels in a biological sample can occur using antibody-based techniques. For example, polypeptide expression in tissues can be studied with classical immunohistological methods (Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., et al., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting polypeptide gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase, and radioisotopes, such as iodine (¹²⁵I, ¹²¹I, carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium (¹¹²In), and technetium (^(99m)Tc), and fluorescent labels, such as fluorescein and rhodamine, and biotin.

The tissue or cell type to be analyzed will generally include those which are known, or suspected, to express the gene of inteest (such as, for example, cancer). The protein isolation methods employed herein may, for example, be such as those described in Harlow and Lane (Harlow, E. and Lane, D., 1988, “Antibodies: A Laboratory Manual”, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.), which is incorporated herein by reference in its entirety. The isolated cells can be derived from cell culture or from a patient. The analysis of cells taken from culture may be a necessary step in the assessment of cells that could be used as part of a cell-based gene therapy technique or, alternatively, to test the effect of compounds on the expression of the gene.

For example, antibodies, or fragments of antibodies, such as those described herein, may be used to quantitatively or qualitatively detect the presence of gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.

In a preferred embodiment, antibodies, or fragments of antibodies directed to any one or all of the predicted epitope domains of the polypeptides of the invention (shown in Table 1B) may be used to quantitatively or qualitatively detect the presence of gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.

In an additional preferred embodiment, antibodies, or fragments of antibodies directed to a conformational epitope of a polypeptide of the invention may be used to quantitatively or qualitatively detect the presence of gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.

The antibodies (or fragments thereof), and/or polypeptides of the present invention may, additionally, be employed histologically, as in immunofluorescence, immunoelectron microscopy or non-immunological assays, for in situ detection of gene products or conserved variants or peptide fragments thereof. In situ detection may be accomplished by removing a histological specimen from a patient, and applying thereto a labeled antibody or polypeptide of the present invention. The antibody (or fragment thereof) or polypeptide is preferably applied by overlaying the labeled antibody (or fragment) onto a biological sample. Through the use of such a procedure, it is possible to determine not only the presence of the gene product, or conserved variants or peptide fragments, or polypeptide binding, but also its distribution in the examined tissue. Using the present invention, those of ordinary skill will readily perceive that any of a wide variety of histological methods (such as staining procedures) can be modified in order to achieve such in situ detection.

Immunoassays and non-immunoassays for gene products or conserved variants or peptide fragments thereof will typically comprise incubating a sample, such as a biological fluid, a tissue extract, freshly harvested cells, or lysates of cells which have been incubated in cell culture, in the presence of a detectably labeled antibody capable of binding gene products or conserved variants or peptide fragments thereof, and detecting the bound antibody by any of a number of techniques well-known in the art.

The biological sample may be brought in contact with and immobilized onto a solid phase support or carrier such as nitrocellulose, or other solid support which is capable of immobilizing cells, cell particles or soluble proteins. The support may then be washed with suitable buffers followed by treatment with the detectably labeled antibody or detectable polypeptide of the invention. The solid phase support may then be washed with the buffer a second time to remove unbound antibody or polypeptide. Optionally the antibody is subsequently labeled. The amount of bound label on solid support may then be detected by conventional means.

By “solid phase support or carrier” is intended any support capable of binding an antigen or an antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite. The nature of the carrier can be either soluble to some extent or insoluble for the purposes of the present invention. The support material may have virtually any possible structural configuration so long as the coupled molecule is capable of binding to an antigen or antibody. Thus, the support configuration may be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface may be flat such as a sheet, test strip, etc. Preferred supports include polystyrene beads. Those skilled in the art will know many other suitable carriers for binding antibody or antigen, or will be able to ascertain the same by use of routine experimentation.

The binding activity of a given lot of antibody or antigen polypeptide may be determined according to well known methods. Those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation.

In addition to assaying polypeptide levels or polynucleotide levels in a biological sample obtained from an individual, polypeptide or polynucleotide can also be detected in vivo by imaging. For example, in one embodiment of the invention, polypeptides and/or antibodies of the invention are used to image diseased cells, such as neoplasms. In another embodiment, polynucleotides of the invention (e.g., polynucleotides complementary to all or a portion of an mRNA) and/or antibodies (e.g., antibodies directed to any one or a combination of the epitopes of a polypeptide of the invention, antibodies directed to a conformational epitope of a polypeptide of the invention, or antibodies directed to the full length polypeptide expressed on the cell surface of a mammalian cell) are used to image diseased or neoplastic cells.

Antibody labels or markers for in vivo imaging of polypeptides of the invention include those detectable by X-radiography, NMR, MRI, CAT-scans or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma. Where in vivo imaging is used to detect enhanced levels of polypeptides for diagnosis in humans, it may be preferable to use human antibodies or “humanized” chimeric monoclonal antibodies. Such antibodies can be produced using techniques described herein or otherwise known in the art. For example methods for producing chimeric antibodies are known in the art. See, for review, Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985).

Additionally, any polypeptides of the invention whose presence can be detected, can be administered. For example, polypeptides of the invention labeled with a radio-opaque or other appropriate compound can be administered and visualized in vivo, as discussed, above for labeled antibodies. Further, such polypeptides can be utilized for in vitro diagnostic procedures.

A polypeptide-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example, ¹³¹I, ¹¹²In, ^(99m)Tc), a radio-opaque substance, or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously or intraperitoneally) into the mammal to be examined for a disorder. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of ^(99m)Tc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the antigenic protein. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments” (Chapter 13 in Tumor imaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).

With respect to antibodies, one of the ways in which an antibody of the present invention can be detectably labeled is by linking the same to a reporter enzyme and using the linked product in an enzyme immunoassay (EIA) (Voller, A., “The Enzyme Linked Immunosorbent Assay (ELISA)”, 1978, Diagnostic Horizons 2:1-7, Microbiological Associates Quarterly Publication, Walkersville, Md.); Voller et al., J. Clin. Pathol. 31:507-520 (1978); Butler, J. E., Meth. Enzymol. 73:482-523 (1981); Maggio, E. (ed.), 1980, Enzyme Immunoassay, CRC Press, Boca Raton, Fla.,; Ishikawa, E. et al., (eds.), 1981, Enzyme Immunoassay, Kgaku Shoin, Tokyo). The reporter enzyme which is bound to the antibody will react with an appropriate substrate, preferably a chromogenic substrate, in such a manner as to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorimetric or by visual means. Reporter enzymes which can be used to detectably label the antibody include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, delta-5-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. Additionally, the detection can be accomplished by calorimetric methods which employ a chromogenic substrate for the reporter enzyme. Detection may also be accomplished by visual comparison of the extent of enzymatic reaction of a substrate in comparison with similarly prepared standards.

Detection may also be accomplished using any of a variety of other immunoassays. For example, by radioactively labeling the antibodies or antibody fragments, it is possible to detect polypeptides through the use of a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by means including, but not limited to, a gamma counter, a scintillation counter, or autoradiography.

It is also possible to label the antibody with a fluorescent compound. When the fluorescently labeled antibody is exposed to light of the proper wave length, its presence can then be detected due to fluorescence. Among the most commonly used fluorescent labeling compounds are fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, ophthaldehyde and fluorescamine.

The antibody can also be detectably labeled using fluorescence emitting metals such as ¹⁵²Eu, or others of the lanthanide series. These metals can be attached to the antibody using such metal chelating groups as diethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA).

The antibody also can be detectably labeled by coupling it to a chemiluminescent compound. The presence of the chemiluminescent-tagged antibody is then determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of particularly useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.

Likewise, a bioluminescent compound may be used to label the antibody of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in, which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence. Important bioluminescent compounds for purposes of labeling are luciferin, luciferase and aequorin.

Methods for Detecting Diseases

In general, a disease may be detected in a patient based on the presence of one or more proteins of the invention and/or polynucleotides encoding such proteins in a biological sample (for example, blood, sera, urine, and/or tumor biopsies) obtained from the patient. In other words, such proteins may be used as markers to indicate the presence or absence of a disease or disorder, including cancer and/or as described elsewhere herein. In addition, such proteins may be useful for the detection of other diseases and cancers. The binding agents provided herein generally permit detection of the level of antigen that binds to the agent in the biological sample. Polynucleotide primers and probes may be used to detect the level of mRNA encoding polypeptides of the invention, which is also indicative of the presence or absence of a disease or disorder, including cancer. In general, polypeptides of the invention should be present at a level that is at least three fold higher in diseased tissue than in normal tissue.

There are a variety of assay formats known to those of ordinary skill in the art for using a binding agent to detect polypeptide markers in a sample. See, e.g., Harlow and Lane, supra. In general, the presence or absence of a disease in a patient may be determined by (a) contacting a biological sample obtained from a patient with a binding agent; (b) detecting in the sample a level of polypeptide that binds to the binding agent; and (c) comparing the level of polypeptide with a predetermined cut-off value.

In a preferred embodiment, the assay involves the use of a binding agent(s) immobilized on a solid support to bind to and remove the polypeptide of the invention from the remainder of the sample. The bound polypeptide may then be detected using a detection reagent that contains a reporter group and specifically binds to the binding agent/polypeptide complex. Such detection reagents may comprise, for example, a binding agent that specifically binds to the polypeptide or an antibody or other agent that specifically binds to the binding agent, such as an anti-immunoglobulin, protein G, protein A or a lectin. Alternatively, a competitive assay may be utilized, in which a polypeptide is labeled with a reporter group and allowed to bind to the immobilized binding agent after incubation of the binding agent with the sample. The extent to which components of the sample inhibit the binding of the labeled polypeptide to the binding agent is indicative of the reactivity of the sample with the immobilized binding agent. Suitable polypeptides for use within such assays include polypeptides of the invention and portions thereof, or antibodies, to which the binding agent binds, as described above.

The solid support may be any material known to those of skill in the art to which polypeptides of the invention may be attached. For example, the solid support may be a test well in a microtiter plate or a nitrocellulose or other suitable membrane. Alternatively, the support may be a bead or disc, such as glass fiberglass, latex or a plastic material such as polystyrene or polyvinylchloride. The support may also be a magnetic particle or a fiber optic sensor, such as those disclosed, for example, in U.S. Pat. No. 5,359,681. The binding agent may be immobilized on the solid support using a variety of techniques known to those of skill in the art, which are amply described in the patent and scientific literature. In the context of the present invention, the term “immobilization” refers to both noncovalent association, such as adsorption, and covalent attachment (which may be a direct linkage between the agent and functional groups on the support or may be a linkage by way of a cross-linking agent). Immobilization by adsorption to a well in a microtiter plate or to a membrane is preferred. In such cases, adsorption may be achieved by contacting the binding agent, in a suitable buffer, with the solid support for the suitable amount of time. The contact time varies with temperature, but is typically between about 1 hour and about 1 day. In general, contacting a well of plastic microtiter plate (such as polystyrene or polyvinylchloride) with an amount of binding agent ranging from about 10 ng to about 10 ug, and preferably about 100 ng to about 1 ug, is sufficient to immobilize an adequate amount of binding agent.

Covalent attachment of binding agent to a solid support may generally be achieved by first reacting the support with a bifunctional reagent that will react with both the support and a functional group, such as a hydroxyl or amino group, on the binding agent. For example, the binding agent may be covalently attached to supports having an appropriate polymer coating using benzoquinone or by condensation of an aldehyde group on the support with an amine and an active hydrogen on the binding partner (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, at A12-A13).

Gene Therapy Methods

Also encompassed by the invention are gene therapy methods for treating or preventing disorders, diseases and conditions. The gene therapy methods relate to the introduction of nucleic acid (DNA, RNA and antisense DNA or RNA) sequences into an animal to achieve expression of the polypeptide of the present invention. This method requires a polynucleotide which codes for a polypeptide of the present invention operatively linked to a promoter and any other genetic elements necessary for the expression of the polypeptide by the target tissue. Such gene therapy and delivery techniques are known in the art, see, for example, WO90/11092, which is herein incorporated by reference.

Thus, for example, cells from a patient may be engineered with a polynucleotide (DNA or RNA) comprising a promoter operably linked to a polynucleotide of the present invention ex vivo, with the engineered cells then being provided to a patient to be treated with the polypeptide of the present invention. Such methods are well-known in the arL For example, see Belldegrun, A., et al., J. Natl. Cancer Inst. 85: 207-216 (1993); Ferrantini, M. et al., Cancer Research 53: 1107-1112 (1993); Ferrantini, M. et al., J. Immunology 153: 4604-4615 (1994); Kaido, T., et al., Int. J. Cancer 60: 221-229 (1995); Ogura, H., et al., Cancer Research 50: 5102-5106 (1990); Santodonato, L., et al., Human Gene Therapy 7:1-10 (1996); Santodonato, L., et al., Gene Therapy 4:1246-1255 (1997); and Zhang, J.-F. et al., Cancer Gene Therapy 3: 31-38 (1996)), which are herein incorporated by reference. In one embodiment, the cells which are engineered are arterial cells. The arterial cells may be reintroduced into the patient through direct injection to the artery, the tissues surrounding the artery, or through catheter injection.

As discussed in more detail below, the polynucleotide constructs can be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, and the like). The polynucleotide constructs may be delivered in a pharmaceutically acceptable liquid or aqueous carrier.

In one embodiment, the polynucleotide of the present invention is delivered as a naked polynucleotide. The term “naked” polynucleotide, DNA or RNA refers to sequences that are free from any delivery vehicle that acts to assist, promote or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. However, the polynucleotide of the present invention can also be delivered in liposome formulations and lipofectin formulations and the like can be prepared by methods well known to those skilled in the art. Such methods are described, for example, in U.S. Pat. Nos. 5,593,972, 5,589,466, and 5,580,859, which are herein incorporated by reference.

The polynucleotide vector constructs used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Appropriate vectors include pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; pSVK3, pBPV, pMSG and pSVL available from Pharmacia; and pEF1/V5, pcDNA3.1, and pRc/CMV2 available from Invitrogen. Other suitable vectors will be readily apparent to the skilled artisan.

Any strong promoter known to those skilled in the art can be used for driving the expression of the polynucleotide sequence. Suitable promoters include adenoviral promoters, such as the adenoviral major late promoter, or heterologous promoters, such as the cytomegalovirus (CMV) promoter, the respiratory syncytial virus (RSV) promoter; inducible promoters, such as the MMT promoter, the metallothionein promoter, heat shock promoters; the albumin promoter; the ApoAI promoter; human globin promoters; viral thymidine kinase promoters, such as the Herpes Simplex thymidine kinase promoter; retroviral LTRs; the b-actin promoter, and human growth hormone promoters. The promoter also may be the native promoter for the polynucleotide of the present invention.

Unlike other gene therapy techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.

The polynucleotide construct can be delivered to the interstitial space of tissues within the an animal, including of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular, fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.

For the naked nucleic acid sequence injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 mg/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration.

The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose. In addition, naked DNA constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.

The naked polynucleotides are delivered by any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, and so-called “gene guns”. These delivery methods are known in the art.

The constructs may also be delivered with delivery vehicles such as viral sequences, viral particles, liposome formulations, lipofectin, precipitating agents, etc. Such methods of delivery are known in the art.

In certain embodiments, the polynucleotide constructs are complexed in a liposome preparation. Liposomal preparations for use in the instant invention include cationic (positively charged), anionic (negatively charged) and neutral preparations. However, cationic liposomes are particularly preferred because a tight charge complex can be formed between the cationic liposome and the polyanionic nucleic acid. Cationic liposomes have been shown to mediate intracellular delivery of plasmid DNA (Felgner et al., Proc. Natl. Acad. Sci. USA (1987) 84:7413-7416, which is herein incorporated by reference); mRNA (Malone et al., Proc. Natl. Acad. Sci. USA (1989) 86:6077-6081, which is herein incorporated by reference); and purified transcription factors (Debs et al., J. Biol. Chem. (1990) 265:10189-10192, which is herein incorporated by reference), in functional form.

Cationic liposomes are readily available. For example, N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes are particularly useful and are available under the trademark Lipofectin, from GIBCO BRL, Grand Island, N.Y. (See, also, Felgner et al., Proc. Natl. Acad. Sci. USA (1987) 84:7413-7416, which is herein incorporated by reference). Other commercially available liposomes include transfectace (DDAB/DOPE) and DOTAP/DOPE (Boehringer).

Other cationic liposomes can be prepared from readily available materials using techniques well known in the art. See, e.g. PCT Publication No. WO 90/11092 (which is herein incorporated by reference) for a description of the synthesis of DOTAP (1,2-bis(oleoyloxy)-3-(trimethylammonio)propane) liposomes. Preparation of DOTMA liposomes is explained in the literature, see, e.g., P. Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417, which is herein incorporated by reference. Similar methods can be used to prepare liposomes from other cationic lipid materials.

Similarly, anionic and neutral liposomes are readily available, such as from Avanti Polar Lipids (Birmingham, Ala.), or can be easily prepared using readily available materials. Such materials include phosphatidyl, choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can also be mixed with the DOTMA and DOTAP starting materials in appropriate ratios. Methods for making liposomes using these materials are well known in the art.

For example, commercially dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), and dioleoylphosphatidyl ethanolamine (DOPE) can be used in various combinations to make conventional liposomes, with or without the addition of cholesterol. Thus, for example, DOPG/DOPC vesicles can be prepared by drying 50 mg each of DOPG and DOPC under a stream of nitrogen gas into a sonication vial. The sample is placed under a vacuum pump overnight and is hydrated the following day with deionized water. The sample is then sonicated for 2 hours in a capped vial, using a Heat Systems model 350 sonicator equipped with an inverted cup (bath type) probe at the maximum setting while the bath is circulated at 15EC. Alternatively, negatively charged vesicles can be prepared without sonication to produce multilamellar vesicles or by extrusion through nucleopore membranes to produce unilamellar vesicles of discrete size. Other methods are known and available to those of skill in the art.

The liposomes can comprise multilamellar vesicles (MLVs), small unilamellar vesicles (SUVs), or large unilamellar vesicles (LUVs), with SUVs being preferred. The various liposome-nucleic acid complexes are prepared using methods well known in the art. See, e.g., Straubinger et al., Methods of Immunology (1983), 101:512-527, which is herein incorporated by reference. For example, MLVs containing nucleic acid can be prepared by depositing a thin film of phospholipid on the walls of a glass tube and subsequently hydrating with a solution of the material to be encapsulated. SUVs are prepared by extended sonication of MLVs to produce a homogeneous population of unilamellar liposomes. The material to be entrapped is added to a suspension of preformed MLVs and then sonicated. When using liposomes containing cationic lipids, the dried lipid film is resuspended in an appropriate solution such as sterile water or an isotonic buffer solution such as 10 mM Tris/NaCl, sonicated, and then the preformed liposomes are mixed directly with the DNA. The liposome and DNA form a very stable complex due to binding of the positively charged liposomes to the cationic DNA. SUVs find use with small nucleic acid fragments. LUVs are prepared by a number of methods, well known in the art. Commonly used methods include Ca²⁺-EDTA chelation (Papahadjopoulos et al., Biochim. Biophys. Acta (1975) 394:483; Wilson et al., Cell 17:77 (1979)); ether injection (Deamer, D. and Bangham, A., Biochim. Biophys. Acta 443:629 (1976); Ostro et al., Biochem Biophys. Res. Commun. 76:836 (1977); Fraley et al., Proc. Natl. Acad. Sci. USA 76:3348 (1979)); detergent dialysis (Enoch, H. and Strittmatter, P., Proc. Natl. Acad. Sci. USA 76:145 (1979)); and reverse-phase evaporation (REV) Fraley et al., J. Biol. Chem. 255:10431 (1980); Szoka, F. and Papahadjopoulos, D., Proc. Natl. Acad. Sci. USA 75:145 (1978); Schaefer-Ridder et al., Science 215:166 (1982)), which are herein incorporated by reference.

Generally, the ratio of DNA to liposomes will be from about 10:1 to about 1:10. Preferably, the ration will be from about 5:1 to about 1:5. More preferably, the ration will be about 3:1 to about 1:3. Still more preferably, the ratio will be about 1:1.

U.S. Pat. No. 5,676,954 (which is herein incorporated by reference) reports on the injection of genetic material, complexed with cationic liposomes carriers, into mice. U.S. Pat. Nos. 4,897,355, 4,946,787, 5,049,386, 5,459,127, 5,589,466, 5,693,622, 5,580,859, 5,703,055, and international publication no. WO 94/9469 (which are herein incorporated by reference) provide cationic lipids for use in transfecting DNA into cells and mammals. U.S. Pat. Nos. 5,589,466, 5,693,622, 5,580,859, 5,703,055, and international publication no. WO 94/9469 provide methods for delivering DNA-cationic lipid complexes to mammals.

In certain embodiments, cells are engineered, ex vivo or in vivo, using a retroviral particle containing RNA which comprises a sequence encoding a polypeptide of the present invention. Retroviruses from which the retroviral plasmid vectors may be derived include, but are not limited to, Moloney Murine Leukemia Virus, spleen necrosis virus, Rous sarcoma Virus, Harvey Sarcoma Virus, avian leukosis virus, gibbon ape leukemia virus, human immunodeficiency virus, Myeloproliferative Sarcoma Virus, and mammary tumor virus.

The retroviral plasmid vector is employed to transduce packaging cell lines to form producer cell lines. Examples of packaging cells which may be transfected include, but are not limited to, the PE501, PA317, R-2, R-AM, PA12, T19-14X, VT-19-17-H2, RCRE, RCRIP, GP+E-86, GP+envAm12, and DAN cell lines as described in Miller, Human Gene Therapy 1:5-14 (1990), which is incorporated herein by reference in its entirety. The vector may transduce the packaging cells through any means known in the arL Such means include, but are not limited to, electroporation, the use of liposomes, and CaPO₄ precipitation. In one alternative, the retroviral plasmid vector may be encapsulated into a liposome, or coupled to a lipid, and then administered to a host.

The producer cell line generates infectious retroviral vector particles which include polynucleotide encoding a polypeptide of the present invention. Such retroviral vector particles then may be employed, to transduce eukaryotic cells, either in vitro or in vivo. The transduced eukaryotic cells will express a polypeptide of the present invention.

In certain other embodiments, cells are engineered, ex vivo or in vivo, with polynucleotide contained in an adenovirus vector. Adenovirus can be manipulated such that it encodes and expresses a polypeptide of the present invention, and at the same time is inactivated in terms of its ability to replicate in a normal lytic viral life cycle. Adenovirus expression is achieved without integration of the viral DNA into the host cell chromosome, thereby alleviating concerns about insertional mutagenesis. Furthermore, adenoviruses have been used as live enteric vaccines for many years with an excellent safety profile (Schwartz et al. Am. Rev. Respir. Dis.109:233-238 (1974)). Finally, adenovirus mediated gene transfer has been demonstrated in a number of instances including transfer of alpha-1-antitrypsin and CFtR to the lungs of cotton rats (Rosenfeld, M. A. et al. (1991) Science 252:431-434; Rosenfeld et al., (1992) Cell 68:143-155). Furthermore, extensive studies to attempt to establish adenovirus as a causative agent in human cancer were uniformly negative (Green, M. et al. (1979) Proc. Natl. Acad. Sci. USA 76:6606).

Suitable adenoviral vectors useful in the present invention are described, for example, in Kozarsky and Wilson, Curr. Opin. Genet. Devel. 3:499-503 (1993); Rosenfeld et al., Cell 68:143-155 (1992); Engelhardt et al., Human Genet. Ther. 4:759-769 (1993); Yang et al., Nature Genet. 7:362-369 (1994); Wilson et al., Nature 365:691-692 (1993); and U.S. Pat. No. 5,652,224, which are herein incorporated by reference. For example, the adenovirus vector Ad2 is useful and can be grown in human 293 cells. These cells contain the E1 region of adenovirus and constitutively express E1a and E1b, which complement the defective adenoviruses by providing the products of the genes deleted from the vector. In addition to Ad2, other varieties of adenovirus (e.g., Ad3, Ad5, and Ad7) are also useful in the present invention.

Preferably, the adenoviruses used in the present invention are replication deficient. Replication deficient adenoviruses require the aid of a helper virus and/or packaging cell line to form infectious particles. The resulting virus is capable of infecting cells and can express a polynucleotide of interest which is operably linked to a promoter, but cannot replicate in most cells. Replication deficient adenoviruses may be deleted in one or more of all or a portion of the following genes: E1a, E1b, E3, E4, E2a, or L1 through L5.

In certain other embodiments, the cells are engineered, ex vivo or in vivo, using an adeno-associated virus (AAV). AAVs are naturally occurring defective viruses that require helper viruses to produce infectious particles (Muzyczka, N., Curr. Topics in Microbiol. Immunol. 158:97 (1992)). It is also one of the few viruses that may integrate its DNA into non-dividing cells. Vectors containing as little as 300 base pairs of AAV can be packaged and can integrate, but space for exogenous DNA is limited to about 4.5 kb. Methods for producing and using such AAVs are known in the art. See, for example, U.S. Pat. Nos. 5,139,941, 5,173,414, 5,354,678, 5,436,146, 5,474,935,5,478,745, and 5,589,377.

For example, an appropriate AAV vector for use in the present invention will include all the sequences necessary for DNA replication, encapsidation, and host-cell integration. The polynucleotide construct is inserted into the AAV vector using standard cloning methods, such as those found in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press (1989). The recombinant AAV vector is then transfected into packaging cells which are infected with a helper virus, using any standard technique, including lipofection, electroporation, calcium phosphate precipitation, etc. Appropriate helper viruses include adenoviruses, cytomegaloviruses, vaccinia viruses, or herpes viruses. Once the packaging cells are transfected and infected, they will produce infectious AAV viral particles which contain the polynucleotide construct. These viral particles are then used to transduce eukaryotic cells, either ex vivo or in vivo. The transduced cells will contain the polynucleotide construct integrated into its genome, and will express a polypeptide of the invention.

Another method of gene therapy involves operably associating heterologous control regions and endogenous polynucleotide sequences (e.g. encoding a polypeptide of the present invention) via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication No. WO 96/29411, published Sep. 26, 1996; International Publication No. WO 94/12650, published Aug. 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), which are herein encorporated by reference. This method involves the activation of a gene which is present in the target cells, but which is not normally expressed in the cells, or is expressed at a lower level than desired.

Polynucleotide constructs are made, using standard techniques known in the art, which contain the promoter with targeting sequences flanking the promoter. Suitable promoters are described herein. The targeting sequence is sufficiently complementary to an endogenous sequence to permit homologous recombination of the promoter-targeting sequence with the endogenous sequence. The targeting sequence will be sufficiently near the 5′ end of the desired endogenous polynucleotide sequence so the promoter will be operably linked to the endogenous sequence upon homologous recombination.

The promoter and the targeting sequences can be amplified using PCR. Preferably, the amplified promoter contains distinct restriction enzyme sites on the 5′ and 3′ ends. Preferably, the 3′ end of the first targeting sequence contains the same restriction enzyme site as the 5′ end of the amplified promoter and the 5′ end of the second targeting sequence contains the same restriction site as the 3′ end of the amplified promoter. The amplified promoter and targeting sequences are digested and ligated together.

The promoter-targeting sequence construct is delivered to the cells, either as naked polynucleotide, or in conjunction with transfection-facilitating agents, such as liposomes, viral sequences, viral particles, whole viruses, lipofection, precipitating agents, etc., described in more detail above. The P promoter-targeting sequence can be delivered by any method, included direct needle injection, intravenous injection, topical administration, catheter infusion, particle accelerators, etc. The methods are described in more detail below.

The promoter-targeting sequence construct is taken up by cells. Homologous recombination between the construct and the endogenous sequence takes place, such that an endogenous sequence is placed under the control of the promoter. The promoter then drives the expression of the endogenous sequence.

The polynucleotide encoding a polypeptide of the present invention may contain a secretory signal sequence that facilitates secretion of the protein. Typically, the signal sequence is positioned in the coding region of the polynucleotide to be expressed towards or at the 5′ end of the coding region. The signal sequence may be homologous or heterologous to the polynucleotide of interest and may be homologous or heterologous to the cells to be transfected. Additionally, the signal sequence may be chemically synthesized using methods known in the art.

Any mode of administration of any of the above-described polynucleotides constructs can be used so long as the mode results in the expression of one or more molecules in an amount sufficient to provide a therapeutic effect. This includes direct needle injection, systemic injection, catheter infusion, biolistic injectors, particle accelerators (i.e., “gene guns”), gelfoam sponge depots, other commercially available depot materials, osmotic pumps (e.g., Alza ninipumps), oral or suppositorial solid (tablet or pill) pharmaceutical formulations, and decanting or topical applications during surgery. For example, direct injection of naked calcium phosphate-precipitated plasmid into rat liver and rat spleen or a protein-coated plasmid into the portal vein has resulted in gene expression of the foreign gene in the rat livers (Kaneda et al., Science 243:375 (1989)).

A preferred method of local administration is by direct injection. Preferably, a recombinant molecule of the present invention complexed with a delivery vehicle is administered by direct injection into or locally within the area of arteries. Administration of a composition locally within the area of arteries refers to injecting the composition centimeters and preferably, millimeters within arteries.

Another method of local administration is to contact a polynucleotide construct of the present invention in or around a surgical wound. For example, a patient can undergo surgery and the polynucleotide construct can be coated on the surface of tissue inside the wound or the construct can be injected into areas of tissue inside the wound.

Therapeutic compositions useful in systemic administration, include recombinant molecules of the present invention complexed to a targeted delivery vehicle of the present invention. Suitable delivery vehicles for use with systemic administration comprise liposomes comprising ligands for targeting the vehicle to a particular site. In specific embodiments, suitable delivery vehicles for use with systemic administration comprise liposomes comprising polypeptides of the invention for targeting the vehicle to a particular site.

Preferred methods of systemic administration, include intravenous injection, aerosol, oral and percutaneous (topical) delivery. Intravenous injections can be performed using methods standard in the art. Aerosol delivery can also be performed using methods standard in the art (see, for example, Stribling et al., Proc. Natl. Acad. Sci. USA 189:11277-11281, 1992, which is incorporated herein by reference). Oral delivery can be performed by complexing a polynucleotide construct of the present invention to a carrier capable of withstanding degradation by digestive enzymes in the gut of an animal. Examples of such carriers, include plastic capsules or tablets, such as those known in the art. Topical delivery can be performed by mixing a polynucleotide construct of the present invention with a lipophilic reagent (e.g., DMSO) that is capable of passing into the skin.

Determining an effective amount of substance to be delivered can depend upon a number of factors including, for example, the chemical structure and biological activity of the substance, the age and weight of the animal, the precise condition requiring treatment and its severity, and the route of administration. The frequency of treatments depends upon a number of factors, such as the amount of polynucleotide constructs administered per dose, as well as the health and history of the subject. The precise amount, number of doses, and timing of doses will be determined by the attending physician or veterinarian.

Therapeutic compositions of the present invention can be administered to any animal, preferably to mammals and birds. Preferred mammals include humans, dogs, cats, mice, rats, rabbits sheep, cattle, horses and pigs, with humans being particularly preferred.

Biological Activities

Polynucleotides or polypeptides, or agonists or antagonists of the present invention, can be used in assays to test for one or more biological activities. If these polynucleotides or polypeptides, or agonists or antagonists of the present invention, do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity. Thus, the polynucleotides and polypeptides, and agonists or antagonists could be used to treat the associated disease.

Members of the secreted family of proteins are believed to be involved in biological activities associated with, for example, cellular signaling. Accordingly, compositions of the invention (including polynucleotides, polypeptides and antibodies of the invention, and fragments and variants thereof) may be used in diagnosis, prognosis, prevention and/or treatment of diseases and/or disorders associated with aberrant activity of secreted polypeptides.

In preferred embodiments, compositions of the invention (including polynucleotides, polypeptides and antibodies of the invention, and fragments and variants thereof) may be used in the diagnosis, prognosis, prevention, treatment, and/or amelioration of diseases and/or disorders relating to the hematopoietic system (e.g., blood coagulation disorders (e.g., hemophilia); blood clotting disorders (e.g., thromboembolism, and pulmonary embolism); fibrinolysis disorders; complement activation disorders (e.g., complement component deficiencies); hematopoietic disorders (e.g., X-linked agammaglobulinemia, anemia); or immune system disorders (e.g., autoimmunity and immunodeficiencies)); and/or as described under “Immune Activity”, “Cardiovascular Disorders”, and “Blood-Related Disorders” below, and neoplastic disorders (e.g., cell migration, prohormone activation, extracellular matrix turnover), and/or as described under “Immune Activity” and “Hyperproliferative Disorders” below.

In certain embodiments, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose and/or prognosticate diseases and/or disorders associated with the tissue(s) in which the polypeptide of the invention is expressed including one, two, three, four, five, or more tissues disclosed in Table 1B.2, column 5 (Tissue Distribution Library Code).

Thus, polynucleotides, translation products and antibodies of the invention are useful in the diagnosis, detection, prevention, prognistication, and/or treatment of diseases and/or disorders associated with activities that include, but are not limited to, prohormone activation, neurotransmitter activity, cellular signaling, cellular proliferation, cellular differentiation, and cell migration.

More generally, polynucleotides, translation products and antibodies corresponding to this gene may be useful for the diagnosis, prognosis, prevention, treatment and/or amelioration of diseases and/or disorders associated with the following system or systems.

Immune Activity

Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in preventing, diagnosing, prognosticating, treating, and/or ameliorating diseases, disorders, and/or conditions of the immune system, by, for example, activating or inhibiting the proliferation, differentiation, or mobilization (chemotaxis) of immune cells. Immune cells develop through a process called hematopoiesis, producing myeloid (platelets, red blood cells, neutrophils, and macrophages) and lymphoid (B and T lymphocytes) cells from pluripotent stem cells. The etiology of these immune diseases, disorders, and/or conditions may be genetic, somatic, such as cancer and some autoimmune diseases, acquired (e.g., by chemotherapy or toxins), or infectious. Moreover, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention can be used as a marker or detector of a particular immune system disease or disorder.

In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to treat diseases and disorders of the immune system and/or to inhibit or enhance an immune response generated by cells associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1B.2, column 5 (Tissue Distribution Library Code).

Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in preventing, diagnosing, prognosticating, treating and/or ameliorating immunodeficiencies, including both congenital and acquired immunodeficiencies. Examples of B cell immunodeficiencies in which immunoglobulin levels B cell function and/or B cell numbers are decreased include: X-linked agammaglobulinemia (Bruton's disease), X-linked infantile agammaglobulinemia, X-linked immunodeficiency with hyper IgM, non X-linked immunodeficiency with hyper IgM, X-linked lymphoproliferative syndrome (XLP), agammaglobulinemia including congenital and acquired agammaglobulinemia, adult onset agammaglobulinemia, late-onset agammaglobulinemia, dysgammaglobulinemia, hypogammaglobulinemia, unspecified hypogammaglobulinemia, recessive agammaglobulinemia (Swiss type), Selective IgM deficiency, selective IgA deficiency, selective IgG subclass deficiencies, IgG subclass deficiency (with or without IgA deficiency), Ig deficiency with increased IgM, IgG and IgA deficiency with increased IgM, antibody deficiency with normal or elevated Igs, Ig heavy chain deletions, kappa chain deficiency, B cell lymphoproliferative disorder (BLPD), common variable immunodeficiency (CVID), common variable immunodeficiency (CVI) (acquired), and transient hypogammaglobulinemia of infancy.

In specific embodiments, ataxia-telangiectasia or conditions associated with ataxia-telangiectasia are detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated using the polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof.

Examples of congenital immunodeficiencies in which T cell and/or B cell function and/or number is decreased include, but are not limited to: DiGeorge anomaly, severe combined immunodeficiencies (SCID) (including, but not limited to, X-linked SCID, autosomal recessive SCID, adenosine deaminase deficiency, purine nucleoside phosphorylase (PNP) deficiency, Class II MHC deficiency (Bare lymphocyte syndrome), Wiskott-Aldrich syndrome, and ataxia telangiectasia), thymic hypoplasia, third and fourth pharyngeal pouch syndrome, 22q11.2 deletion, chronic mucocutaneous candidiasis, natural killer cell deficiency (NK), idiopathic CD4+ T-lymphocytopenia, immunodeficiency with predominant T cell defect (unspecified), and unspecified immunodeficiency of cell mediated immunity.

In specific embodiments, DiGeorge anomaly or conditions associated with DiGeorge anomaly are prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using polypeptides or polynucleotides of the invention, or antagonists or agonists thereof.

Other immunodeficiencies that may be prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof, include, but are not limited to, chronic granulomatous disease, Chédiak-Higashi syndrome, myeloperoxidase deficiency, leukocyte glucose-6-phosphate dehydrogenase deficiency, X-linked lymphoproliferative syndrome (XLP), leukocyte adhesion deficiency, complement component deficiencies (including C1, C2, C3, C4, C5, C6, C7, C8 and/or C9 deficiencies), reticular dysgenesis, thymic alymphoplasia-aplasia, immunodeficiency with thymoma, severe congenital leukopenia, dysplasia with immunodeficiency, neonatal neutropenia, short limbed dwarfism, and Nezelof syndrome-combined immunodeficiency with Igs.

In a preferred embodiment, the immunodeficiencies and/or conditions associated with the immunodeficiencies recited above are prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

In a preferred embodiment polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used as an agent to boost immunoresponsiveness among immunodeficient individuals. In specific embodiments, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used as an agent to boost immunoresponsiveness among B cell and/or T cell immunodeficient individuals.

The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in preventing, detecting, diagnosing, prognosticating, treating and/or ameliorating autoimmune disorders. Many autoimmune disorders result from inappropriate recognition of self as foreign material by immune cells. This inappropriate recognition results in an immune response leading to the destruction of the host tissue. Therefore, the administration of polynucleotides and polypeptides of the invention that can inhibit an immune response, particularly the proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing autoimmune disorders.

Autoimmune diseases or disorders that may be prevented, detected, diagnosed, prognosticated, treated, and/or ameliorated by polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, one or more of the following: systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, autoimmune thyroiditis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, hemolytic anemia, thrombocytopenia, autoimmune thrombocytopenia purpura, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenia purpura, purpura (e.g., Henloch-Scoenlein purpura), autoimmunocytopenia, Goodpasture's syndrome, Pemphigus vulgaris, myasthenia gravis, Grave's disease (hyperthyroidism), and insulin-resistant diabetes mellitus.

Additional disorders that are likely to have an autoimmune component that may be prevented, detected, diagnosed, prognosticated, treated and/or ameliorated with the compositions of the invention include, but are not limited to, type II collagen-induced arthritis, antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, relapsing polychondritis, rheumatic heart disease, neuritis, uveitis ophthalmia, polyendocrinopathies, Reiter's Disease, Stiff-Man Syndrome, autoimmune pulmonary inflammation, autism, Guillain-Barre Syndrome, insulin dependent diabetes mellitus, and autoimmune inflammatory eye disorders.

Additional disorders that are likely to have an autoimmune component that may be prevented, detected, diagnosed, prognosticated, treated and/or ameliorated with the compositions of the invention include, but are not limited to, scleroderma with anti-collagen antibodies (often characterized, e.g., by nucleolar and other nuclear antibodies), mixed connective tissue disease (often characterized, e.g., by antibodies to extractable nuclear antigens (e.g., ribonucleoprotein)), polymyositis (often characterized, e.g., by nonhistone ANA), pernicious anemia (often characterized, e.g., by antiparietal cell, microsomes, and intrinsic factor antibodies), idiopathic Addison's disease (often characterized, e.g., by humoral and cell-mediated adrenal cytotoxicity, infertility (often characterized, e.g., by antispermatozoal antibodies), glomerulonephritis (often characterized, e.g., by glomerular basement membrane antibodies or immune complexes), bullous pemphigoid (often characterized, e.g., by IgG and complement in basement membrane), Sjogren's syndrome (often characterized, e.g., by multiple tissue antibodies, and/or a specific nonhistone ANA (SS-B)), diabetes mellitus (often characterized, e.g., by cell-mediated and humoral islet cell antibodies), and adrenergic drug resistance (including adrenergic drug resistance with asthma or cystic fibrosis) (often characterized, e.g., by beta-adrenergic receptor antibodies).

Additional disorders that may have an autoimmune component that may be prevented, detected, diagnosed, prognosticated, treated and/or ameliorated with the compositions of the invention include, but are not limited to, chronic active hepatitis (often characterized, e.g., by smooth muscle antibodies), primary biliary cirrhosis (often characterized, e.g., by mitochondria antibodies), other endocrine gland failure (often characterized, e.g., by specific tissue antibodies in some cases), vitiligo (often characterized, e.g., by melanocyte antibodies), vasculitis (often characterized, e.g., by Ig and complement in vessel walls and/or low serum complement), post-MI (often characterized, e.g., by myocardial antibodies), cardiotomy syndrome (often characterized, e.g., by myocardial antibodies), urticaria (often characterized, e.g., by IgG and IgM antibodies to IgE), atopic dermatitis (often characterized, e.g., by IgG and IgM antibodies to IgE), asthma (often characterized, e.g., by IgG and IgM antibodies to IgE), and many other inflammatory, granulomatous, degenerative, and atrophic disorders.

In a preferred embodiment, the autoimmune diseases and disorders and/or conditions associated with the diseases and disorders recited above are prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using for example, antagonists or agonists, polypeptides or polynucleotides, or antibodies of the present invention. In a specific preferred embodiment, rheumatoid arthritis is prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

In another specific preferred embodiment, systemic lupus erythematosus is prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention. In another specific preferred embodiment, idiopathic thrombocytopenia purpura is prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

In another specific preferred embodiment IgA nephropathy is prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

In a preferred embodiment, the autoimmune diseases and disorders and/or conditions associated with the diseases and disorders recited above are prevented, detected, diagnosed, prognosticated, treated and/or ameliorated using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.

In preferred embodiments, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a immunosuppressive agent(s).

Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating diseases, disorders, and/or conditions of hematopoietic cells. Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used to increase differentiation and proliferation of hematopoietic cells, including the pluripotent stem cells, in an effort to treat or prevent those diseases, disorders, and/or conditions associated with a decrease in certain (or many) types hematopoietic cells, including but not limited to, leukopenia, neutropenia, anemia, and thrombocytopenia. Alternatively, Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used to increase differentiation and proliferation of hematopoietic cells, including the pluripotent stem cells, in an effort to treat or prevent those diseases, disorders, and/or conditions associated with an increase in certain (or many) types of hematopoietic cells, including but not limited to, histiocytosis.

Allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems, may also be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated using polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof. Moreover, these molecules can be used to treat, prevent, prognose, and/or diagnose anaphylaxis, hypersensitivity to an antigenic molecule, or blood group incompatibility.

Additionally, polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof, may be used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate IgE-mediated allergic reactions. Such allergic reactions include, but are not limited to, asthma, rhinitis, and eczema. In specific embodiments, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to modulate IgE concentrations in vitro or in vivo.

Moreover, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention have uses in the detection, prevention, diagnosis, prognostication, treatment, and/or amelioration of inflammatory conditions. For example, since polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists of the invention may inhibit the activation, proliferation and/or differentiation of cells involved in an inflammatory response, these molecules can be used to prevent and/or treat chronic and acute inflammatory conditions. Such inflammatory conditions include, but are not limited to, for example, inflammation associated with infection (e.g., septic shock, sepsis, or systemic inflammatory response syndrome), ischemia-reperfusion injury, endotoxin lethality, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine induced lung injury, inflammatory bowel disease, Crohn's disease, over production of cytokines (e.g., TNF or IL-1.), respiratory disorders (e.g., asthma and allergy); gastrointestinal disorders (e.g., inflammatory bowel disease); cancers (e.g., gastric, ovarian, lung, bladder, liver, and breast); CNS disorders (e.g., multiple sclerosis; ischemic brain injury and/or stroke, traumatic brain injury, neurodegenerative disorders (e.g., Parkinson's disease and Alzheimer's disease); AIDS-related dementia; and prion disease); cardiovascular disorders (e.g., atherosclerosis, myocarditis, cardiovascular disease, and cardiopulmonary bypass complications); as well as many additional diseases, conditions, and disorders that are characterized by inflammation (e.g., hepatitis, rheumatoid arthritis, gout, trauma, pancreatitis, sarcoidosis, dermatitis, renal ischemia-reperfusion injury, Grave's disease, systemic lupus erythematosus, diabetes mellitus, and allogenic transplant rejection).

Because inflammation is a fundamental defense mechanism, inflammatory disorders can effect virtually any tissue of the body. Accordingly, polynucleotides, polypeptides, and antibodies of the invention, as well as agonists or antagonists thereof, have uses in the treatment of tissue-specific inflammatory disorders, including, but not limited to, adrenalitis, alveolitis, angiocholecystitis, appendicitis, balanitis, blepharitis, bronchitis, bursitis, carditis, cellulitis, cervicitis, cholecystitis, chorditis, cochlitis, colitis, conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachitis, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, labyrinthitis, laryngitis, lymphangitis, mastitis, media otitis, meningitis, metritis, mucitis, myocarditis, myosititis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, peritendonitis, peritonitis, pharyngitis, phlebitis, poliomyelitis, prostatitis, pulpitis, retinitis, rhinitis, salpingitis, scleritis, sclerochoroiditis, scrotitis, sinusitis, spondylitis, steatitis, stomatitis, synovitis, syringitis, tendonitis, tonsillitis, urethritis, and vaginitis.

In specific embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, are useful to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate organ transplant rejections and graft-versus-host disease. Organ rejection occurs by host immune cell destruction of the transplanted tissue through an immune response. Similarly, an immune response is also involved in GVHD, but, in this case, the foreign transplanted immune cells destroy the host tissues. Polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, that inhibit an immune response, particularly the activation, proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing organ rejection or GVHD. In specific embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, that inhibit an immune response, particularly the activation, proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing experimental allergic and hyperacute xenograft rejection.

In other embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, are useful to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate immune complex diseases, including, but not limited to, serum sickness, post streptococcal glomeralonephritis, polyarteritis nodosa, and immune complex-induced vasculitis.

Polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the invention can be used to treat, detect, and/or prevent infectious agents. For example, by increasing the immune response, particularly increasing the proliferation activation and/or differentiation of B and/or T cells, infectious diseases may be treated, detected, and/or prevented. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may also directly inhibit the infectious agent (refer to section of application listing infectious agents, etc), without necessarily eliciting an immune response.

In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a vaccine adjuvant that enhances immune responsiveness to an antigen. In a specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance tumor-specific immune responses.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-viral immune responses. Anti-viral immune responses that may be enhanced using the compositions of the invention as an adjuvant, include virus and virus associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a virus, disease, or symptom selected from the group consisting of: AIDS, meningitis, Dengue, EBV, and hepatitis (e.g., hepatitis B). In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to a virus, disease, or symptom selected from the group consisting of: HIV/AIDS, respiratory syncytial virus, Dengue, rotavirus, Japanese B encephalitis, influenza A and B, parainfluenza, measles, cytomegalovirus, rabies, Junin, Chikungunya, Rift Valley Fever, herpes simplex, and yellow fever.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-bacterial or anti-fungal immune responses. Anti-bacterial or anti-fungal immune responses that may be enhanced using the compositions of the invention as an adjuvant, include bacteria or fungus and bacteria or fungus associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a bacteria or fungus, disease, or symptom selected from the group consisting of: tetanus, Diphtheria, botulism, and meningitis type B.

In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to a bacteria or fungus, disease, or symptom selected from the group consisting of: Vibrio cholerae, Mycobacterium leprae, Salmonella typhi, Salmonella paratyphi, Meisseria meningitidis, Streptococcus pneumoniae, Group B streptococcus, Shigella spp., Enterotoxigenic Escherichia coli, Enterohemorrhagic E. coli, and Borrelia burgdorferi.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-parasitic immune responses. Anti-parasitic immune responses that may be enhanced using the compositions of the invention as an adjuvant, include parasite and parasite associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a parasite. In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to Plasmodium (malaria) or Leishmania.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed to treat infectious diseases including silicosis, sarcoidosis, and idiopathic pulmonary fibrosis; for example, by preventing the recruitment and activation of mononuclear phagocytes.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an antigen for the generation of antibodies to inhibit or enhance immune mediated responses against polypeptides of the invention.

In one embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are administered to an animal (e.g., mouse, rat, rabbit, hamster, guinea pig, pigs, micro-pig, chicken, camel, goat, horse, cow, sheep, dog, cat, non-human primate, and human, most preferably human) to boost the immune system to produce increased quantities of one or more antibodies (e.g., IgG, IgA, IgM, and IgE), to induce higher affinity antibody production and immunoglobulin class switching (e.g., IgG, IgA, IgM, and IgE), and/or to increase an immune response.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a stimulator of B cell responsiveness to pathogens.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an activator of T cells.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent that elevates the immune status of an individual prior to their receipt of immunosuppressive therapies.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to induce higher affinity antibodies.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to increase serum immunoglobulin concentrations.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to accelerate recovery of immunocompromised individuals.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among aged populations and/or neonates.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an immune system enhancer prior to, during, or after bone marrow transplant and/or other transplants (e.g., allogeneic or xenogeneic organ transplantation). With respect to transplantation, compositions of the invention may be administered prior to, concomitant with, and/or after transplantation. In a specific embodiment, compositions of the invention are administered after transplantation, prior to the beginning of recovery of T-cell populations. In another specific embodiment, compositions of the invention are first administered after transplantation after the beginning of recovery of T cell populations, but prior to full recovery of B cell populations.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among individuals having an acquired loss of B cell function. Conditions resulting in an acquired loss of B cell function that may be ameliorated or treated by administering the polypeptides, antibodies, polynucleotides and/or agonists or antagonists thereof, include, but are not limited to, HIV Infection, AIDS, bone marrow transplant, and B cell chronic lymphocytic leukemia (CLL).

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among individuals having a temporary immune deficiency. Conditions resulting in a temporary immune deficiency that may be ameliorated or treated by administering the polypeptides, antibodies, polynucleotides and/or agonists or antagonists thereof, include, but are not limited to, recovery from viral infections (e.g., influenza), conditions associated with malnutrition, recovery from infectious mononucleosis, or conditions associated with stress, recovery from measles, recovery from blood transfusion, and recovery from surgery.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a regulator of antigen presentation by monocytes, dendritic cells, and/or Bells. In one embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention enhance antigen presentation or antagonizes antigen presentation in vitro or in vivo. Moreover, in related embodiments, said enhancement or antagonism of antigen presentation may be useful as an anti-tumor treatment or to modulate the immune system.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to direct an individual's immune system towards development of a humoral response (i.e. TH2) as opposed to a TH1 cellular response.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means to induce tumor proliferation and thus make it more susceptible to anti-neoplastic agents. For example, multiple myeloma is a slowly dividing disease and is thus refractory to virtually all anti-neoplastic regimens. If these cells were forced to proliferate more rapidly their susceptibility profile would likely change.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a stimulator of B cell production in pathologies such as AIDS, chronic lymphocyte disorder and/or Common Variable Immunodificiency.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for generation and/or regeneration of lymphoid tissues following surgery, trauma or genetic defect In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used in the pretreatment of bone marrow samples prior to transplant.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a gene-based therapy for genetically inherited disorders resulting in immuno-incompetence/immunodeficiency such as observed among SCID patients.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of activating monocytes/macrophages to defend against parasitic diseases that effect monocytes such as Leishmania

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of regulating secreted cytokines that are elicited by polypeptides of the invention.

In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used in one or more of the applications decribed herein, as they may apply to veterinary medicine.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of blocking various aspects of immune responses to foreign agents or self. Examples of diseases or conditions in which blocking of certain aspects of immune responses may be desired include autoimmune disorders such as lupus, and arthritis, as well as immunoresponsiveness to skin allergies, inflammation, bowel disease, injury and diseases/disorders associated with pathogens.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for preventing the B cell proliferation and Ig secretion associated with autoimmune diseases such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus and multiple sclerosis.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a inhibitor of B and/or T cell migration in endothelial cells. This activity disrupts tissue architecture or cognate responses and is useful, for example in disrupting immune responses, and blocking sepsis.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for chronic hypergammaglobulinemia evident in such diseases as monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom's disease, related idiopathic monoclonal gammopathies, and plasmacytomas.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed for instance to inhibit polypeptide chemotaxis and activation of macrophages and their precursors, and of neutrophils, basophils, B lymphocytes and some T-cell subsets, e.g., activated and CD8 cytotoxic T cells and natural killer cells, in certain autoimmune and chronic inflammatory and infective diseases. Examples of autoimmune diseases are described herein and include multiple sclerosis, and insulin-dependent diabetes.

The polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed to treat idiopathic hyper-eosinophilic syndrome by, for example, preventing eosinophil production and migration.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used to enhance or inhibit complement mediated cell lysis.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used to enhance or inhibit antibody dependent cellular cytotoxicity.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed for treating atherosclerosis, for example, by preventing monocyte infiltration in the artery wall.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed to treat adult respiratory distress syndrome (ARDS).

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be useful for stimulating wound and tissue repair, stimulating angiogenesis, and/or stimulating the repair of vascular or lymphatic diseases or disorders. Additionally, agonists and antagonists of the invention may be used to stimulate the regeneration of mucosal surfaces.

In a specific embodiment, polynucleotides or polypeptides, and/or agonists thereof are used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate a disorder characterized by primary or acquired immunodeficiency, deficient serum immunoglobulin production, recurrent infections, and/or immune system dysfunction. Moreover, polynucleotides or polypeptides, and/or agonists thereof may be used to treat or prevent infections of the joints, bones, skin, and/or parotid glands, blood-borne infections (e.g., sepsis, meningitis, septic arthritis, and/or osteomyelitis), autoimmune diseases (e.g., those disclosed herein), inflammatory disorders, and malignancies, and/or any disease or disorder or condition associated with these infections, diseases, disorders and/or malignancies) including, but not limited to, CVID, other primary immune deficiencies, HIV disease, CLL, recurrent bronchitis, sinusitis, otitis media, conjunctivitis, pneumonia, hepatitis, meningitis, herpes zoster (e.g., severe herpes zoster), and/or pneumocystis carnii. Other diseases and disorders that may be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated with polynucleotides or polypeptides, and/or agonists of the present invention include, but are not limited to, H[V infection, HTLV-BLV infection, lymphopenia, phagocyte bactericidal dysfunction anemia, thrombocytopenia, and hemoglobinuria.

In another embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention are used to treat, and/or diagnose an individual having common variable immunodeficiency disease (“CVID”; also known as “acquired agammaglobulinemia” and “acquired hypogarnmaglobulinemia”) or a subset of this disease.

In a specific embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate cancers or neoplasms including immune cell or immune tissue-related cancers or neoplasms. Examples of cancers or neoplasms that may be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated by polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic anemia (ALL) Chronic lymphocyte leukemia, plasmacytomas, multiple myeloma, Burkitt's lymphoma, EBV-transformed diseases, and/or diseases and disorders described in the section entitled “Hyperproliferative Disorders” elsewhere herein.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for decreasing cellular proliferation of Large B-cell Lymphomas.

In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of decreasing the involvement of B cells and Ig associated with Chronic Myelogenous Leukemia.

In specific embodiments, the compositions of the invention are used as an agent to boost immunoresponsiveness among B cell immunodeficient individuals, such as, for example, an individual who has undergone a partial or complete splenectomy.

Antagonists of the invention include, for example, binding and/or inhibitory antibodies, antisense nucleic acids, ribozymes or soluble forms of the polypeptides of the present invention (e.g., Fc fusion protein; see, e.g., Example 9). Agonists of the invention include, for example, binding or stimulatory antibodies, and soluble forms of the polypeptides (e.g., Fc fusion proteins; see, e.g., Example 9). polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed in a composition with a pharmaceutically acceptable carrier, e.g., as described herein.

In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are administered to an animal (including, but not limited to, those listed above, and also including transgenic animals) incapable of producing functional endogenous antibody molecules or having an otherwise compromised endogenous immune system, but which is capable of producing human immunoglobulin molecules by means of a reconstituted or partially reconstituted immune system from another animal (see, e.g., published PCr Application Nos. WO98/24893, WO/9634096, WO/9633735, and WO/9110741). Administration of polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention to such animals is useful for the generation of monoclonal antibodies against the polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention.

Blood-Related Disorders

The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to modulate hemostatic (the stopping of bleeding) or thrombolytic (clot dissolving) activity. For example, by increasing hemostatic or thrombolytic activity, polynucleotides or polypeptides, and/or agonists or antagonists of the present invention could be used to treat or prevent blood coagulation diseases, disorders, and/or conditions (e.g., afibrinogenemia, factor deficiencies, hemophilia), blood platelet diseases, disorders, and/or conditions (e.g., thrombocytopenia), or wounds resulting from trauma, surgery, or other causes. Alternatively, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention that can decrease hemostatic or thrombolytic activity could be used to inhibit or dissolve clotting. These molecules could be important in the treatment or prevention of heart attacks (infarction), strokes, or scarring.

In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate thrombosis, arterial thrombosis, venous thrombosis, thromboembolism, pulmonary embolism, atherosclerosis, myocardial infarction, transient ischemic attack, unstable angina. In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used for the prevention of occulsion of saphenous grafts, for reducing the risk of periprocedural thrombosis as might accompany angioplasty procedures, for reducing the risk of stroke in patients with atrial fibrillation including nonrheumatic atrial fibrillation, for reducing the risk of embolism associated with mechanical heart valves and or mitral valves disease. Other uses for the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention, include, but are not limited to, the prevention of occlusions in extrcorporeal devices (e.g., intravascular canulas, vascular access shunts in hemodialysis patients, hemodialysis machines, and cardiopulmonary bypass machines).

In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate diseases and disorders of the blood and/or blood forming organs associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1B.2, column 5 (Tissue Distribution Library Code).

The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to modulate hematopoietic activity (the formation of blood cells). For example, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to increase the quantity of all or subsets of blood cells, such as, for example, erythrocytes, lymphocytes (B or T cells), myeloid cells (e.g., basophils, eosinophils, neutrophils, mast cells, macrophages) and platelets. The ability to decrease the quantity of blood cells or subsets of blood cells may be useful in the detection, prevention, diagnosis, prognostication, treatment, and/or amelioration of anemias and leukopenias described below. Alternatively, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to decrease the quantity of all or subsets of blood cells, such as, for example, erythrocytes, lymphocytes (B or T cells), myeloid cells (e.g., basophils, eosinophils, neutrophils, mast cells, macrophages) and platelets. The ability to decrease the quantity of blood cells or subsets of blood cells may be useful in the detection, prevention, diagnosis, prognostication, treatment, and/or amelioration of leukocytoses, such as, for example eosinophilia.

The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate blood dyscrasia.

Anemias are conditions in which the number of red blood cells or amount of hemoglobin (the protein that carries oxygen) in them is below normal. Anemia may be caused by excessive bleeding, decreased red blood cell production, or increased red blood cell destruction (hemolysis). The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating anemias. Anemias that may be treated detect, prevented, diagnosed, prognosticated, treated, and/or ameliorated by the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include iron deficiency anemia, hypochromic anemia, microcytic anemia, chlorosis, hereditary siderob; astic anemia, idiopathic acquired sideroblastic anemia, red cell aplasia, megaloblastic anemia (e.g., pernicious anemia, (vitamin B12 deficiency) and folic acid deficiency anemia), aplastic anemia, hemolytic anemias (e.g., autoimmune helolytic anemia, microangiopathic hemolytic anemia, and paroxysmal nocturnal hemoglobinuria). The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating anemias associated with diseases including but not limited to, anemias associated with systemic lupus erythematosus, cancers, lymphomas, chronic renal disease, and enlarged spleens. The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating anemias arising from drug treatments such as anemias associated with methyldopa, dapsone, and/or sulfadrugs. Additionally, rhe polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating anemias associated with abnormal red blood cell architecture including but not limited to, hereditary spherocytosis, hereditary elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, and sickle cell anemia.

The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating hemoglobin abnormalities, (e.g., those associated with sickle cell anemia, hemoglobin C disease, hemoglobin S—C disease, and hemoglobin E disease). Additionally, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating thalassemias, including, but not limited to major and minor forms of alpha-thalassemia and beta-thalassemia.

In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating bleeding disorders including, but not limited to, thrombocytopenia (e.g., idiopathic thrombocytopenic purpura, and thrombotic thrombocytopenic purpura), Von Willebrand's disease, hereditary platelet disorders (e.g., storage pool disease such as Chediak-Higashi and Hermansky-Pudlak syndromes, thromboxane A2 dysfunction, thromboasthenia, and BemardSoulier syndrome), hemolytic-uremic syndrome, hemophelias such as hemophelia A or Factor VII deficiency and Christmas disease or Factor IX deficiency, Hereditary Hemorhhagic Telangiectsia, also known as Rendu-Osler-Weber syndrome, allergic purpura (Henoch Schonlein purpura) and disseminated intravascular coagulation.

The effect of the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention on the clotting time of blood may be monitored using any of the clotting tests known in the art including, but not limited to, whole blood partial thromboplastin time (PTT), the activated partial thromboplastin time (aPTT), the activated clotting time (ACI), the recalcified activated clotting time, or the Lee-White Clotting time.

Several diseases and a variety of drugs can cause platelet dysfunction. Thus, in a specific embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating acquired platelet dysfunction such as platelet dysfunction accompanying kidney failure, leukemia, multiple myeloma, cirrhosis of the liver, and systemic lupus erythematosus as well as platelet dysfunction associated with drug treatments, including treatment with aspirin, ticlopidine, nonsteroidal anti-inflammatory drugs (used for arthritis, pain, and sprains), and penicillin in high doses.

In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating diseases and disorders characterized by or associated with increased or decreased numbers of white blood cells. Leukopenia occurs when the number of white blood cells decreases below normal. Leukopenias include, but are not limited to, neutropenia and lymphocytopenia. An increase in the number of white blood cells compared to normal is known as leukocytosis. The body generates increased numbers of white blood cells during infection. Thus, leukocytosis may simply be a normal physiological parameter that reflects infection. Alternatively, leukocytosis may be an indicator of injury or other disease such as cancer. Leokocytoses, include but are not limited to, eosinophilia, and accumulations of macrophages. In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating leukopenia. In other specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating leukocytosis.

Leukopenia may be a generalized decreased in all types of white blood cells, or may be a specific depletion of particular types of white blood cells. Thus, in specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating decreases in neutrophil numbers, known as neutropenia. Neutropenias that may be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated by the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, infantile genetic agranulocytosis, familial neutropenia, cyclic neutropenia, neutropenias resulting from or associated with dietary deficiencies (e.g., vitamin B 12 deficiency or folic acid deficiency), neutropenias resulting from or associated with drug treatments (e.g., antibiotic regimens such as penicillin treatment, sulfonamide treatment, anticoagulant treatment, anticonvulsant drugs, anti-thyroid drugs, and cancer chemotherapy), and neutropenias resulting from increased neutrophil destruction that may occur in association with some bacterial or viral infections, allergic disorders, autoimmune diseases, conditions in which an individual has an enlarged spleen (e.g., Felty syndrome, malaria and sarcoidosis), and some drug treatment regimens.

The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating lymphocytopenias (decreased numbers of B and/or T lymphocytes), including, but not limited lymphocytopenias resulting from or associated with stress, drug treatments (e.g., drug treatment with corticosteroids, cancer chemotherapies, and/or radiation therapies), AIDS infection and/or other diseases such as, for example, cancer, rheumatoid arthritis, systemic lupus erythematosus, chronic infections, some viral infections and/or hereditary disorders (e.g., DiGeorge syndrome, Wiskott-Aldrich Syndome, severe combined immunodeficiency, ataxia telangiectsia).

The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating diseases and disorders associated with macrophage numbers and/or macrophage function including, but not limited to, Gaucher's disease, Niemann-Pick disease, Letterer-Siwe disease and Hand-Schuller-Christian disease.

In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating diseases and disorders associated with eosinophil numbers and/or eosinophil function including, but not limited to, idiopathic hypereosinophilic syndrome, eosinophilia-myalgia syndrome, and Hand-Schuller-Christian disease.

In yet another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating leukemias and lymphomas including, but not limited to, acute lymphocytic (lymphpblastic) leukemia (ALL), acute myeloid (myelocytic, myelogenous, myeloblastic, or myelomonocytic) leukemia, chronic lymphocytic leukemia (e.g., B cell leukemias, T cell leukemias, Sezary syndrome, and Hairy cell leukenia), chronic myelocytic (myeloid, myelogenous, or granulocytic) leukemia, Hodgkin's lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, and mycosis fungoides.

In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating diseases and disorders of plasma cells including, but not limited to, plasma cell dyscrasias, monoclonal gammaopathies, monoclonal gammopathies of undetermined significance, multiple myeloma, macroglobulinemia, Waldenstrom's macroglobulinemia, cryoglobulinemia, and Raynaud's phenomenon.

In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating myeloproliferative disorders, including but not limited to, polycythemia vera, relative polycythemia, secondary polycythemia, myelofibrosis, acute myelofibrosis, agnogenic myelod metaplasia, thrombocythemia, (including both primary and seconday thrombocythemia) and chronic myelocytic leukemia

In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as a treatment prior to surgery, to increase blood cell production.

In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to enhance the migration, phagocytosis, superoxide production, antibody dependent cellular cytotoxicity of neutrophils, eosionophils and macrophages.

In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase the number of stem cells in circulation prior to stem cells pheresis. In another specific embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase the number of stem cells in circulation prior to platelet pheresis.

In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase cytokine production.

In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating primary hematopoietic and hematologic disorders.

Hyperproliferative Disorders

In certain embodiments, polynucleotides or polypeptides, or agonists or antagonists of the present invention can be used to treat or detect hyperproliferative disorders, including neoplasms. Polynucleotides or polypeptides, or agonists or antagonists of the present invention may inhibit the proliferation of the disorder through direct or indirect interactions. Alternatively, Polynucleotides or polypeptides, or agonists or antagonists of the present invention may proliferate other cells which can inhibit the hyperproliferative disorder.

For example, by increasing an immune response, particularly increasing antigenic qualities of the hyperproliferative disorder or by proliferating, differentiating, or mobilizing T-cells, hyperproliferative disorders can be treated. This immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, decreasing an immune response may also be a method of treating hyperproliferative disorders, such as a chemotherapeutic agent.

Examples of hyperproliferative disorders that can be treated or detected by polynucleotides or polypeptides, or agonists or antagonists of the present invention include, but are not limited to neoplasms located in the: colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvis, skin, soft tissue, spleen, thorax, and urogenital tract.

Similarly, other hyperproliferative disorders can also be treated or detected by polynucleotides or polypeptides, or agonists or antagonists of the present invention. Examples of such hyperproliferative disorders include, but are not limited to: Acute Childhood Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, Adult (Primary) Hepatocellular Cancer, Adult (Primary) Liver Cancer, Adult Acute Lymphocytic Leukemia, Adult Acute Myeloid Leukemia, Adult Hodgkin's Disease, Adult Hodgkin's Lymphoma, Adult Lymphocytic Leukemia, Adult Non-Hodgkin's Lymphoma, Adult Primary Liver Cancer, Adult Soft Tissue Sarcoma, AIDS-Related Lymphoma, AIDS-Related Malignancies, Anal Cancer, Astrocytoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumors, Breast Cancer, Cancer of the Renal Pelvis and Ureter, Central Nervous System (Primary) Lymphoma, Central Nervous System Lymphoma, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Childhood (Primary) Hepatocellular Cancer, Childhood (Primary) Liver Cancer, Childhood Acute Lymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, Childhood Brain Stem Glioma, Childhood Cerebellar Astrocytoma, Childhood Cerebral Astrocytoma, Childhood Extracranial Germ Cell Tumors, Childhood Hodgkin's Disease, Childhood Hodgkin's Lymphoma, Childhood Hypothalamic and Visual Pathway Glioma, Childhood Lymphoblastic Leukemia, Childhood Medulloblastoma, Childhood Non-Hodgkin's Lymphoma, Childhood Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood Primary Liver Cancer, Childhood Rhabdomyosarcoma, Childhood Soft Tissue Sarcoma, Childhood Visual Pathway and Hypothalamic Glioma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Colon Cancer, Cutaneous T-Cell Lymphoma, Endocrine Pancreas Islet Cell Carcinoma, Endometrial Cancer, Ependymoma, Epithelial Cancer, Esophageal Cancer, Ewing's Sarcoma and Related Tumors, Exocrine Pancreatic Cancer, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Female Breast Cancer, Gaucher's Disease, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Tumors, Germ Cell Tumors, Gestational Trophoblastic Tumor, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular Cancer, Hodgkin's Disease, Hodgkin's Lymphoma, Hypergammaglobulinemia, Hypopharyngeal Cancer, Intestinal Cancers, Intraocular Melanoma, Islet Cell Carcinoma, Islet Cell Pancreatic Cancer, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Liver Cancer, Lung Cancer, Lymphoproliferative Disorders, Macroglobulinemia, Male Breast Cancer, Malignant Mesothelioma, Malignant Thymoma, Medulloblastoma, Melanoma, Mesothelioma, Metastatic Occult Primary Squamous Neck Cancer, Metastatic Primary Squamous Neck Cancer, Metastatic Squamous Neck Cancer, Multiple Myeloma, Multiple Myeloma/Plasma Cell Neoplasm, Myelodysplastic Syndrome, Myelogenous Leukemia, Myeloid Leukemia, Myeloproliferative Disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin's Lymphoma During Pregnancy, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Occult Primary Metastatic Squamous Neck Cancer, Oropharyngeal Cancer, Osteo-/Malignant Fibrous Sarcoma, Osteosarcoma/Malignant Fibrous Histiocytoma, Osteosarcoma/Malignant Fibrous Histiocytoma of Bone, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Pancreatic Cancer, Paraproteinemias, Purpura, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Primry Central Nervous System Lymphoma, Priry Liver Cancer, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Renal Pelvis and Ureter Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoidosis Sarcomas, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Neck Cancer, Stomach Cancer, Supratentorial Primitive Neuroectodermal and Pineal Tumors, T-Cell Lymphoma, Testicular Cancer, Thymoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Transitional Renal Pelvis and Ureter Cancer, Trophoblastic Tumors, Ureter and Renal Pelvis Cell Cancer, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma, Vulvar Cancer, Waldenstrom's Macroglobulinemia, Wilms' Tumor, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.

In another preferred embodiment, polynucleotides or polypeptides, or agonists or antagonists of the present invention are used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate premalignant conditions and to prevent progression to a neoplastic or malignant state, including but not limited to those disorders described above. Such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp. 68-79.)

Hyperplasia is a form of controlled cell proliferation, involving an increase in cell number in a tissue or organ, without significant alteration in structure or function. Hyperplastic disorders which can be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, angiofollicular mediastinal lymph node hyperplasia, angiolymphoid hyperplasia with eosinophilia, atypical melanocytic hyperplasia, basal cell hyperplasia, benign giant lymph node hyperplasia, cementum hyperplasia, congenital adrenal hyperplasia, congenital sebaceous hyperplasia, cystic hyperplasia, cystic hyperplasia of the breast, denture hyperplasia, ductal hyperplasia, endometrial hyperplasia, fibromuscular hyperplasia, focal epithelial hyperplasia, gingival hyperplasia, inflammatory fibrous hyperplasia, inflammatory papillary hyperplasia, intravascular papillary endothelial hyperplasia, nodular hyperplasia of prostate, nodular regenerative hyperplasia, pseudoepitheliomatous hyperplasia, senile sebaceous hyperplasia, and verrucous hyperplasia.

Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell. Metaplastic disorders which can be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, agnogenic myeloid metaplasia, apocrine metaplasia, atypical metaplasia, autoparenchymatous metaplasia, connective tissue metaplasia, epithelial metaplasia, intestinal metaplasia, metaplastic anemia, metaplastic ossification, metaplastic polyps, myeloid metaplasia, primary myeloid metaplasia, secondary myeloid metaplasia, squamous metaplasia, squamous metaplasia of amnion, and symptomatic myeloid metaplasia.

Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism. Dysplasia characteristically occurs where there exists chronic irritation or inflammation. Dysplastic disorders which can be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis hemimelia, dysplasia epiphysialis multiplex, dysplasia epiphysialis punctata, epithelial dysplasia, faciodigitogenital dysplasia, familial fibrous dysplasia of jaws, familial white folded dysplasia, fibromuscular dysplasia, fibrous dysplasia of bone, florid osseous dysplasia, hereditary renal-retinal dysplasia, hidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammary dysplasia, mandibulofacial dysplasia, metaphysial dysplasia, Mondini dysplasia, monostotic fibrous dysplasia, mucoepithelial dysplasia, multiple epiphysial dysplasia, oculoauriculovertebral dysplasia, oculodentodigital dysplasia, oculovertebral dysplasia, odontogenic dysplasia, ophthalmomandibulomelic dysplasia, periapical cemental dysplasia, polyostotic fibrous dysplasia, pseudoachondroplastic spondyloepiphysial dysplasia, retinal dysplasia, septo-optic dysplasia, spondyloepiphysial dysplasia, and ventriculoradial dysplasia.

Additional pre-neoplastic disorders which can be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, benign dysproliferative disorders (e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps, colon polyps, and esophageal dysplasia), leukoplakia, keratoses, Bowen's disease, Farmer's Skin, solar cheilitis, and solar keratosis.

In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose and/or prognosticate disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1B.2, column 5 (Tissue Distribution Library Code).

In another embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention conjugated to a toxin or a radioactive isotope, as described herein, may be used to treat cancers and neoplasms, including, but not limited to those described herein. In a further preferred embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention conjugated to a toxin or a radioactive isotope, as described herein, may be used to treat acute myelogenous leukemia.

Additionally, polynucleotides, polypeptides, and/or agonists or antagonists of the invention may affect apoptosis, and therefore, would be useful in treating a number of diseases associated with increased cell survival or the inhibition of apoptosis. For example, diseases associated with increased cell survival or the inhibition of apoptosis that could be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include cancers (such as follicular lymphomas, carcinomas with p53 mutations, and hormone-dependent tumors, including, but not limited to colon cancer, cardiac tumors, pancreatic cancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi's sarcoma and ovarian cancer); autoimmune disorders such as, multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) and viral infections (such as herpes viruses, pox viruses and adenoviruses), inflammation, graft v. host disease, acute graft rejection, and chronic graft rejection.

In preferred embodiments, polynucleotides, polypeptides, and/or agonists or antagonists of the invention are used to inhibit growth, progression, and/or metastasis of cancers, in particular those listed above.

Additional diseases or conditions associated with increased cell survival that could be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, emangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.

Diseases associated with increased apoptosis that could be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include AIDS; neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, cerebellar degeneration and brain tumor or prior associated disease); autoimmune disorders (such as, multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) myelodysplastic syndromes (such as aplastic anemia), graft v. host disease, ischemic injury (such as that caused by myocardial infarction, stroke and reperfusion injury), liver injury (e.g., hepatitis related liver injury, ischemia/reperfusion injury, cholestosis (bile duct injury) and liver cancer); toxin-induced liver disease (such as that caused by alcohol), septic shock, cachexia and anorexia

Hyperproliferative diseases and/or disorders that could be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include, but are not limited to, neoplasms located in the liver, abdomen, bone, breast, digestive system, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous system (central and peripheral), lymphatic system, pelvis, skin, soft tissue, spleen, thorax, and urogenital tract.

Similarly, other hyperproliferative disorders can also be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention. Examples of such hyperproliferative disorders include, but are not limited to: hypergammaglobulinemia, lymphoproliferative disorders, paraproteinemias, purpura, sarcoidosis, Sezary Syndrome, Waldenstron's macroglobulinemia, Gaucher's Disease, histiocytosis, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.

Another preferred embodiment utilizes polynucleotides of the present invention to inhibit aberrant cellular division, by gene therapy using the present invention, and/or protein fusions or fragments thereof.

Thus, the present invention provides a method for treating cell proliferative disorders by inserting into an abnormally proliferating cell a polynucleotide of the present invention, wherein said polynucleotide represses said expression.

Another embodiment of the present invention provides a method of treating cell-proliferative disorders in individuals comprising administration of one or more active gene copies of the present invention to an abnormally proliferating cell or cells. In a preferred embodiment, polynucleotides of the present invention is a DNA construct comprising a recombinant expression vector effective in expressing a DNA sequence encoding said polynucleotides. In another preferred embodiment of the present invention, the DNA construct encoding the poynucleotides of the present invention is inserted into cells to be treated utilizing a retrovirus, or more preferably an adenoviral vector (See G J. Nabel, et. al., PNAS 1999 96: 324-326, which is hereby incorporated by reference). In a most preferred embodiment, the viral vector is defective and will not transform non-proliferating cells, only proliferating cells. Moreover, in a preferred embodiment, the polynucleotides of the present invention inserted into proliferating cells either alone, or in combination with or fused to other polynucleotides, can then be modulated via an external stimulus (i.e. magnetic, specific small molecule, chemical, or drug administration, etc.), which acts upon the promoter upstream of said polynucleotides to induce expression of the encoded protein product. As such the beneficial therapeutic affect of the present invention may be expressly modulated (i.e. to increase, decrease, or inhibit expression of the present invention) based upon said external stimulus.

Polynucleotides of the present invention may be useful in repressing expression of oncogenic genes or antigens. By “repressing expression of the oncogenic genes” is intended the suppression of the transcription of the gene, the degradation of the gene transcript (pre-message RNA), the inhibition of splicing, the destruction of the messenger RNA, the prevention of the post-translational modifications of the protein, the destruction of the protein, or the inhibition of the normal function of the protein.

For local administration to abnormally proliferating cells, polynucleotides of the present invention may be administered by any method known to those of skill in the art including, but not limited to transfection, electroporation, microinjection of cells, or in vehicles such as liposomes, lipofectin, or as naked polynucleotides, or any other method described throughout the specification. The polynucleotide of the present invention may be delivered by known gene delivery systems such as, but not limited to, retroviral vectors (Gilboa, J. Virology 44:845 (1982); Hocke, Nature 320:275 (1986); Wilson, et al., Proc. Natl. Acad. Sci. U.S.A. 85:3014), vaccinia virus system (Chakrabarty et al., Mol. Cell Biol. 5:3403 (1985) or other efficient DNA delivery systems (Yates et al., Nature 313:812 (1985)) known to those skilled in the art. These references are exemplary only and are hereby incorporated by reference. In order to specifically deliver or transfect cells which are abnormally proliferating and spare non-dividing cells, it is preferable to utilize a retrovirus, or adenoviral (as described in the art and elsewhere herein) delivery system known to those of skill in the art. Since host DNA replication is required for retroviral DNA to integrate and the retrovirus will be unable to self replicate due to the lack of the retrovirus genes needed for its life cycle. Utilizing such a retroviral delivery system for polynucleotides of the present invention will target said gene and constructs to abnormally proliferating cells and will spare the non-dividing normal cells.

The polynucleotides of the present invention may be delivered directly to cell proliferative disorder/disease sites in internal organs, body cavities and the like by use of imaging devices used to guide an injecting needle directly to the disease site. The polynucleotides of the present invention may also be administered to disease sites at the time of surgical intervention.

By “cell proliferative disease” is meant any human or animal disease or disorder, affecting any one or any combination of organs, cavities, or body parts, which is characterized by single or multiple local abnormal proliferations of cells, groups of cells, or tissues, whether benign or malignant.

Any amount of the polynucleotides of the present invention may be administered as long as it has a biologically inhibiting effect on the proliferation of the treated cells. Moreover, it is possible to administer more than one of the polynucleotide of the present invention simultaneously to the same site. By “biologically inhibiting” is meant partial or total growth inhibition as well as decreases in the rate of proliferation or growth of the cells. The biologically inhibitory dose may be determined by assessing the effects of the polynucleotides of the present invention on target malignant or abnormally proliferating cell growth in tissue culture, tumor growth in animals and cell cultures, or any other method known to one of ordinary skill in the art.

The present invention is further directed to antibody-based therapies which involve administering of anti-polypeptides and anti-polynucleotide antibodies to a mammalian, preferably human, patient for treating one or more of the described disorders. Methods for producing anti-polypeptides and anti-polynucleotide antibodies polyclonal and monoclonal antibodies are described in detail elsewhere herein. Such antibodies may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.

A summary of the ways in which the antibodies of the present invention may be used therapeutically includes binding polynucleotides or polypeptides of the present invention locally or systemically in the body or by direct cytotoxicity of the antibody, e.g. as mediated by complement (CDC) or by effector cells (ADCC). Some of these approaches are described in more detail below. Armed with the teachings provided herein, one of ordinary skill in the art will know how to use the antibodies of the present invention for diagnosis, prognosis, monitoring, or therapeutic purposes without undue experimentation.

In particular, the antibodies, fragments and derivatives of the present invention are useful for treating a subject having or developing cell proliferative and/or differentiation disorders as described herein. Such treatment comprises administering a single or multiple doses of the antibody, or a fragment, derivative, or a conjugate thereof.

The antibodies of this invention may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors, for example., which serve to increase the number or activity of effector cells which interact with the antibodies.

It is preferred to use high affinity and/or potent in vivo inhibiting and/or neutralizing antibodies against polypeptides or polynucleotides of the present invention, fragments or regions thereof, for both immunoassays directed to and therapy of disorders related to polynucleotides or polypeptides, including fragements thereof, of the present invention. Such antibodies, fragments, or regions, will preferably have an affinity for polynucleotides or polypeptides, including fragements thereof. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10⁻⁶M, 10⁻⁶M, 5×10⁻⁷M, 10⁻⁷M, 5×10⁻⁸M, 10⁻⁸M, 5×10⁻⁹M, 10⁻⁹M, 5×10⁻¹⁰M, 10⁻¹⁰M, 5×10⁻¹¹M, 10⁻¹¹M, 5×10⁻¹²M, 10⁻¹²M, 5×10⁻¹³M, 10⁻¹³M, 5×10⁻¹⁴M, 10⁻¹⁴M, 5×10⁻¹⁵M, and 10⁻¹⁵M.

Moreover, polypeptides of the present invention are useful in inhibiting the angiogenesis of proliferative cells or tissues, either alone, as a protein fusion, or in combination with other polypeptides directly or indirectly, as described elsewhere herein. In a most preferred embodiment, said anti-angiogenesis effect may be achieved indirectly, for example, through the inhibition of hematopoietic, tumor-specific cells, such as tumor-associated macrophages (See Joseph I B, et al. J Natl Cancer Inst, 90(21):1648-53 (1998), which is hereby incorporated by reference). Antibodies directed to polypeptides or polynucleotides of the present invention may also result in inhibition of angiogenesis directly, or indirectly (See Witte L, et al., Cancer Metastasis Rev. 17(2):155-61 (1998), which is hereby incorporated by reference)).

Polypeptides, including protein fusions, of the present invention, or fragments thereof may be useful in inhibiting proliferative cells or tissues through the induction of apoptosis. Said polypeptides may act either directly, or indirectly to induce apoptosis of proliferative cells and tissues, for example in the activation of a death-domain receptor, such as tumor necrosis factor (TNF) receptor-1, CD95 (Fas/APO-1), TNF-receptor-related apoptosis-mediated protein (TRAMP) and TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 and -2 (See Schulze-Osthoff K, et. al., Eur J Biochem 254(3):439-59 (1998), which is hereby incorporated by reference). Moreover, in another preferred embodiment of the present invention, said polypeptides may induce apoptosis through other mechanisms, such as in the activation of other proteins which will activate apoptosis, or through stimulating the expression of said proteins, either alone or in combination with small molecule drugs or adjuviants, such as apoptonin, galectins, thioredoxins, anti-inflammatory proteins (See for example, Mutat Res 400(1-2):447-55 (1998), Med Hypotheses. 50(5):423-33 (1998), Chem Biol Interact April 24; 111-112:23-34 (1998), J Mol Med. 76(6):402-12 (1998), Int J Tissue React;20(1):3-15 (1998), which are all hereby incorporated by reference).

Polypeptides, including protein fusions to, or fragments thereof, of the present invention are useful in inhibiting the metastasis of proliferative cells or tissues. Inhibition may occur as a direct result of administering polypeptides, or antibodies directed to said polypeptides as described elsewere herein, or indirectly, such as activating the expression of proteins known to inhibit metastasis, for example alpha 4 integrins, (See, e.g., Curr Top Microbiol Immunol 1998;231:125-41, which is hereby incorporated by reference). Such thereapeutic affects of the present invention may be achieved either alone, or in combination with small molecule drugs or adjuvants.

In another embodiment, the invention provides a method of delivering compositions containing the polypeptides of the invention (e.g., compositions containing polypeptides or polypeptide antibodes associated with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs) to targeted cells expressing the polypeptide of the present invention. Polypeptides or polypeptide antibodes of the invention may be associated with with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/or covalent interactions.

Polypeptides, protein fusions to, or fragments thereof, of the present invention are useful in enhancing the immunogenicity and/or antigenicity of proliferating cells or tissues, either directly, such as would occur if the polypeptides of the present invention ‘vaccinated’ the immune response to respond to proliferative antigens and immunogens, or indirectly, such as in activating the expression of proteins known to enhance the immune response (e.g. chemokines), to said antigens and immunogens.

Cardiovascular Disorders

Polynucleotides or polypeptides, or agonists or antagonists of the present invention, may be used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate cardiovascular diseases and disorders, including, but not limited to, peripheral artery disease, such as limb ischemia.

Cardiovascular disorders include, but are not limited to, cardiovascular abnormalities, such as arterio-arterial fistula, arteriovenous fistula, cerebral arteriovenous malformations, congenital heart defects, pulmonary atresia, and Scimitar Syndrome. Congenital heart defects include, but are not limited to, aortic coarctation, cor triatriatum, coronary vessel anomalies, crisscross heart, dextrocardia, patent ductus arteriosus, Ebstein's anomaly, Eisemnenger complex, hypoplastic left heart syndrome, levocardia, tetralogy of fallot, transposition of great vessels, double outlet right ventricle, tricuspid atresia, persistent truncus arteriosus, and heart septal defects, such as aortopulmonary septal defect, endocardial cushion defects, Lutembacher's Syndrome, trilogy of Fallot, ventricular heart septal defects.

Cardiovascular disorders also include, but are not limited to, heart disease, such as arrhythmias, carcinoid heart disease, high cardiac output, low cardiac output, cardiac tamponade, endocarditis (including bacterial), heart aneurysm, cardiac arrest, congestive heart failure, congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, heart hypertrophy, congestive cardiomyopathy, left ventricular hypertrophy, right ventricular hypertrophy, post-infarction heart rupture, ventricular septal rupture, heart valve diseases, myocardial diseases, myocardial ischemia, pericardial effusion, pericarditis (including constrictive and tuberculous), pneumopericardium, postpericardiotomy syndrome, pulmonary heart disease, rheumatic heart disease, ventricular dysfunction, hyperemia, cardiovascular pregnancy complications, Scimitar Syndrome, cardiovascular syphilis, and cardiovascular tuberculosis.

Arrhythmias include, but are not limited to, sinus arrhythmia, atrial fibrillation, atrial flutter, bradycardia, extrasystole, Adams-Stokes Syndrome, bundle-branch block, sinoatrial block, long QT syndrome, parasystole, Lown-Ganong-Levine Syndrome, Mahaim-type pre-excitation syndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome, tachycardias, and ventricular fibrillation. Tachycardias include paroxysmal tachycardia, supraventricular tachycardia, accelerated idioventricular rhythm, atrioventricular nodal reentry tachycardia, ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrial nodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, and ventricular tachycardia.

Heart valve diseases include, but are not limited to, aortic valve insufficiency, aortic valve stenosis, hear murmurs, aortic valve prolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valve insufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valve insufficiency, pulmonary valve stenosis, tricuspid atresia, ticuspid valve insufficiency, and tricuspid valve stenosis.

Myocardial diseases include, but are not limited to, alcoholic cardiomyopathy, congestive cardiomyopathy, hypertrophic cardiomyopathy, aortic subvalvular stenosis, pulmonary subvalvular stenosis, restrictive cardiomyopathy, Chagas cardiomyopathy, endocardial fibroelastosis, endomyocardial fibrosis, Kearns Syndrome, myocardial reperfusion injury, and myocarditis.

Myocardial ischemias include, but are not limited to, coronary disease, such as angina pectoris, coronary aneurysm, coronary arteriosclerosis, coronary thrombosis, coronary vasospasm, myocardial infarction and myocardial stunning.

Cardiovascular diseases also include vascular diseases such as aneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis, Hippel-Lindau Disease, Klippel-Trenaunay-Weber Syndrome, Sturge-Weber Syndrome, angioneurotic edema, aortic diseases, Takayasu's Arteritis, aortitis, Leriche's Syndrome, arterial occlusive diseases, arteritis, enarteritis, polyarteritis nodosa, cerebrovascular disorders, diabetic angiopathies, diabetic retinopathy, embolisms, thrombosis, erythromelalgia, hemorrhoids, hepatic veno-occlusive disease, hypertension, hypotension, ischemia, peripheral vascular diseases, phlebitis, pulmonary veno-occlusive disease, Raynaud's disease, CREST syndrome, retinal vein occlusion, Scimitar syndrome, superior vena cava syndrome, telangiectasia, atacia telangiectasia, hereditary hemorrhagic telangiectasia, varicocele, varicose veins, varicose ulcer, vasculitis, and venous insufficiency.

Aneurysms include, but are not limited to, dissecting aneurysms, false aneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms, cerebral aneurysms; coronary aneurysms, heart aneurysms, and iliac aneurysms.

Arterial occlusive diseases include, but are not limited to, arteriosclerosis, intermittent claudication, carotid stenosis, fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoya disease, renal artery obstruction, retinal artery occlusion, and thromboangiitis obliterans.

Cerebrovascular disorders include, but are not limited to, carotid artery diseases, cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenous malformation, cerebral artery diseases, cerebral embolism and thrombosis, carotid artery thrombosis, sinus thrombosis, Wallenberg's syndrome, cerebral hemorrhage, epidural hematoma, subdural hematoma, subaraxhnoid hemorrhage, cerebral infarction, cerebral ischemia (including transient), subclavian steal syndrome, periventricular leukomalacia, vascular headache, cluster headache, migraine, and vertebrobasilar insufficiency.

Embolisms include, but are not limited to, air embolisms, amniotic fluid embolisms, cholesterol embolisms, blue toe syndrome, fat embolisms, pulmonary embolisms, and thromoboembolisms. Thrombosis include, but are not limited to, coronary thrombosis, hepatic vein thrombosis, retinal vein occlusion, carotid artery thrombosis, sinus thrombosis, Wallenberg's syndrome, and thrombophlebitis.

Ischemic disorders include, but are not limited to, cerebral ischemia, ischemic colitis, compartment syndromes, anterior compartment syndrome, myocardial ischemia, reperfusion injuries, and peripheral limb ischemia. Vasculitis includes, but is not limited to, aortitis, arteritis, Behcet's Syndrome, Churg-Strauss Syndrome, mucocutaneous lymph node syndrome, thromboangiitis obliterans, hypersensitivity vasculitis, Schoenlein-Henoch purpura, allergic cutaneous vasculitis, and Wegener's granulomatosis.

Polypeptides may be administered using any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, biolistic injectors, particle accelerators, gelfoam sponge depots, other commercially available depot materials, osmotic pumps, oral or suppositorial solid pharmaceutical formulations, decanting or topical applications during surgery, aerosol delivery. Such methods are known in the art. Polypeptides may be administered as part of a Therapeutic, described in more detail below. Methods of delivering polynucleotides are described in more detail herein.

Diseases at the Cellular Level

Diseases associated with increased cell survival or the inhibition of apoptosis that could be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated using polynucleotides or polypeptides, as well as antagonists or agonists of the present invention, include cancers (such as follicular lymphomas, carcinomas with p53 mutations, and hormone-dependent tumors, including, but not limited to colon cancer, cardiac tumors, pancreatic cancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi's sarcoma and ovarian cancer); autoimmune disorders (such as, multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) and viral infections (such as herpes viruses, pox viruses and adenoviruses), inflammation, graft v. host disease, acute graft rejection, and chronic graft rejection.

In preferred embodiments, polynucleotides, polypeptides, and/or antagonists of the invention are used to inhibit growth, progression, and/or metasis of cancers, in particular those listed above.

Additional diseases or conditions associated with increased cell survival that could be treated or detected by polynucleotides or polypeptides, or agonists or antagonists of the present invention include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.

Diseases associated with increased apoptosis that could be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated using polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, include, but are not limited to, AIDS; neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Retinitis pigmentosa, Cerebellar degeneration and brain tumor or prior associated disease); autoimmune disorders (such as, multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) myelodysplastic syndromes (such as aplastic anemia), graft v. host disease, ischemic injury (such as that caused by myocardial infarction, stroke and reperfusion injury), liver injury (e.g., hepatitis related liver injury, ischemia/reperfusion injury, cholestosis (bile duct injury) and liver cancer); toxin-induced liver disease (such as that caused by alcohol), septic shock, cachexia and anorexia.

Wound Healing and Epithelial Cell Proliferation

In accordance with yet a further aspect of the present invention, there is provided a process for utilizing polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, for therapeutic purposes, for example, to stimulate epithelial cell proliferation and basal keratinocytes for the purpose of wound healing, and to stimulate hair follicle production and healing of dermal wounds. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may be clinically useful in stimulating wound healing including surgical wounds, excisional wounds, deep wounds involving damage of the dermis and epidermis, eye tissue wounds, dental tissue wounds, oral cavity wounds, diabetic ulcers, dermal ulcers, cubitus ulcers, arterial ulcers, venous stasis ulcers, burns resulting from heat exposure or chemicals, and other abnormal wound healing conditions such as uremia, malnutrition, vitamin deficiencies and complications associated with systemic treatment with steroids, radiation therapy and antineoplastic drugs and antimetabolites. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to promote dermal reestablishment subsequent to dermal loss

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to increase the adherence of skin grafts to a wound bed and to stimulate re-epithelialization from the wound bed. The following are types of grafts that polynucleotides or polypeptides, agonists or antagonists of the present invention, could be used to increase adherence to a wound bed: autografts, artificial skin, allografts, autodermic graft, autoepdermic grafts, avacular grafts, Blair-Brown grafts, bone graft, brephoplastic grafts, cutis graft, delayed graft, dermic graft, epidermic graft, fascia graft, full thickness graft, heterologous graft, xenograft, homologous graft, hyperplastic graft, lamellar graft, mesh graft, mucosal graft, Ollier-Thiersch graft, omenpal graft, patch graft, pedicle graft, penetrating graft, split skin graft, thick split graft. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, can be used to promote skin strength and to improve the appearance of aged skin.

It is believed that polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, will also produce changes in hepatocyte proliferation, and epithelial cell proliferation in the lung, breast, pancreas, stomach, small intestine, and large intestine. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could promote proliferation of epithelial cells such as sebocytes, hair follicles, hepatocytes, type II pneumocytes, mucin-producing goblet cells, and other epithelial cells and their progenitors contained within the skin, lung, liver, and gastrointestinal tract. Polynucleotides or polypeptides, agonists or antagonists of the present invention, may promote proliferation of endothelial cells, keratinocytes, and basal keratinocytes.

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could also be used to reduce the side effects of gut toxicity that result from radiation, chemotherapy treatments or viral infections. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may have a cytoprotective effect on the small intestine mucosa. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may also stimulate healing of mucositis (mouth ulcers) that result from chemotherapy and viral infections.

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could further be used in full regeneration of skin in full and partial thickness skin defects, including burns, (i.e., repopulation of hair follicles, sweat glands, and sebaceous glands), treatment of other skin defects such as psoriasis. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to treat epidermolysis bullosa, a defect in adherence of the epidermis to the underlying dermis which results in frequent, open and painful blisters by accelerating reepithelialization of these lesions. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could also be used to treat gastric and doudenal ulcers and help heal by scar formation of the mucosal lining and regeneration of glandular mucosa and duodenal mucosal lining more rapidly. Inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, are diseases which result in destruction of the mucosal surface of the small or large intestine, respectively. Thus, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to promote the resurfacing of the mucosal surface to aid more rapid healing and to prevent progression of inflammatory bowel disease. Treatment with polynucleotides or polypeptides, agonists or antagonists of the present invention, is expected to have a significant effect on the production of mucus throughout the gastrointestinal tract and could be used to protect the intestinal mucosa from injurious substances that are ingested or following surgery. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to treat diseases associate with the under expression.

Moreover, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to prevent and heal damage to the lungs due to various pathological states. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, which could stimulate proliferation and differentiation and promote the repair of alveoli and brochiolar epithelium to prevent or treat acute or chronic lung damage. For example, emphysema, which results in the progressive loss of aveoli, and inhalation injuries, i.e., resulting from smoke inhalation and burns, that cause necrosis of the bronchiolar epithelium and alveoli could be effectively treated using polynucleotides or polypeptides, agonists or antagonists of the present invention. Also, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to stimulate the proliferation of and differentiation of type II pneumocytes, which may help treat or prevent disease such as hyaline membrane diseases, such as infant respiratory distress syndrome and bronchopulmonary displasia, in premature infants.

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could stimulate the proliferation and differentiation of hepatocytes and, thus, could be used to alleviate or treat liver diseases and pathologies such as fulminant liver failure caused by cirrhosis, liver damage caused by viral hepatitis and toxic substances (i.e., acetaminophen, carbon tetraholoride and other hepatotoxins known in the art).

In addition, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used treat or prevent the onset of diabetes mellitus. In patients with newly diagnosed Types I and II diabetes, where some islet cell function remains, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to maintain the islet function so as to alleviate, delay or prevent permanent manifestation of the disease. Also, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used as an auxiliary in islet cell transplantation to improve or promote islet cell function.

Infectious Disease

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention can be used to treat or detect infectious agents. For example, by increasing the immune response, particularly increasing the proliferation and differentiation of B and/or T cells, infectious diseases may be treated. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may also directly inhibit the infectious agent, without necessarily eliciting an immune response.

Viruses are one example of an infectious agent that can cause disease or symptoms that can be treated or detected by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention. Examples of viruses, include, but are not limited to Examples of viruses, include, but are not limited to the following DNA and RNA viruses and viral families: Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae, Coronaviridae, Dengue, EBV, HIV, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes Zoster), Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Orthomyxoviridae (e.g., Influenza A, Influenza B, and parainfluenza), Papiloma virus, Papovaviridae, Parvoviridae, Picornaviridae, Poxyiridae (such as Smallpox or Vaccinia), Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-L HTLV-II, Lentivirus), and Togaviridae (e.g., Rubivirus). Viruses falling within these families can cause a variety of diseases or symptoms, including, but not limited to: arthritis, bronchiollitis, respiratory syncytial virus, encephalitis, eye infections (e.g., conjunctivitis, keratitis), chronic fatigue syndrome, hepatitis (A, B, C, E, Chronic Active, Delta), Japanese B encephalitis, Junin, Chikungunya, Rift Valley fever, yellow fever, meningitis, opportunistic infections (e.g., AIDS), pneumonia, Burkitt's Lymphoma, chickenpox, hemorrhagic fever, Measles, Mumps, Parainfluenza, Rabies, the common cold, Polio, leukemia, Rubella, sexually transmitted diseases, skin diseases (e.g., Kaposi's, warts), and viremia. polynucleotides or polypeptides, or agonists or antagonists of the invention, can be used to treat or detect any of these symptoms or diseases. In specific embodiments, polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat: meningitis, Dengue, EBV, and/or hepatitis (e.g., hepatitis B). In an additional specific embodiment polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat patients nonresponsive to one or more other commercially available hepatitis vaccines. In a further specific embodiment polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat AIDS.

Similarly, bacterial and fungal agents that can cause disease or symptoms and that can be treated or detected by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention include, but not limited to, the following Gram-Negative and Gram-positive bacteria, bacterial families, and fungi: Actinomyces (e.g., Norcardia), Acinetobacter, Cryptococcus neoformans, Aspergillus, Bacillaceae (e.g., Bacillus anthrasis), Bacteroides (e.g., Bacteroides fragilis), Blastomycosis, Bordetella, Borrelia (e.g., Borrelia burgdorferi), Brucella, Candidia, Campylobacter, Chlamydia, Clostridium (e.g., Clostridium botulinum, Clostridium dificile, Clostridium perfringens, Clostridium tetani), Coccidioides, Corynebacterium (e.g., Corynebacterium diptheriae), Cryptococcus, Dermatocycoses, E. coli (e.g., Enterotoxigenic E. coli and Enterohemorrhagic E. coli), Enterobacter (e.g. Enterobacter aerogenes), Enterobacteriaceae (Klebsiella, Salmonella (e.g., Salmonella typhi, Salmonella enteritidis, Salmonella typhi), Serratia, Yersinia, Shigella), Erysipelothrix, Haemophilus (e.g., Haemophilus influenza type B), Helicobacter, Legionella (e.g., Legionella pneumophila), Leptospira, Listeria (e.g., Listeria monocytogenes), Mycoplasma, Mycobacterium (e.g., Mycobacterium leprae and Mycobacterium tuberculosis), Vibrio (e.g., Vibrio cholerae), Neisseriaceae (e.g., Neisseria gonorrhea, Neisseria meningitidis), Pasteurellacea, Proteus, Pseudomonas (e.g., Pseudomonas aeruginosa), Rickettsiaceae, Spirochetes (e.g., Treponema spp., Leptospira spp., Borrelia spp.), Shigella spp., Staphylococcus (e.g., Staphylococcus aureus), Meningiococcus, Pneumococcus and Streptococcus (e.g., Streptococcus pneumoniae and Groups A, B, and C Streptococci), and Ureaplasmas. These bacterial, parasitic, and fungal families can cause diseases or symptoms, including, but not limited to: antibiotic-resistant infections, bacteremia, endocarditis, septicemia, eye infections (e.g., conjunctivitis), uveitis, tuberculosis, gingivitis, bacterial diarrhea, opportunistic infections (e.g., AIDS related infections), paronychia, prosthesis-related infections, dental caries, Reiter's Disease, respiratory tract infections, such as Whooping Cough or Empyema, sepsis, Lyme Disease, Cat-Scratch Disease, dysentery, paratyphoid fever, food poisoning, Legionella disease, chronic and acute inflammation, erythema, yeast infections, typhoid, pneumonia, gonorrhea, meningitis (e.g., mengitis types A and B), chlamydia, syphillis, diphtheria, leprosy, brucellosis, peptic ulcers, anthrax, spontaneous abortions, birth defects, pneumonia, lung infections, ear infections, deafness, blindness, lethargy, malaise, vomiting, chronic diarrhea, Crohn's disease, colitis, vaginosis, sterility, pelvic inflammatory diseases, candidiasis, paratuberculosis, tuberculosis, lupus, botulism, gangrene, tetanus, impetigo, Rheumatic Fever, Scarlet Fever, sexually transmitted diseases, skin diseases (e.g., cellulitis, dermatocycoses), toxemia, urinary tract infections, wound infections, noscomial infections. Polynucleotides or polypeptides, agonists or antagonists of the invention, can be used to treat or detect any of these symptoms or diseases. In specific embodiments, polynucleotides, polypeptides, agonists or antagonists of the invention are used to treat: tetanus, diptheria, botulism, and/or meningitis type B.

Moreover, parasitic agents causing disease or symptoms that can be detected, prevented, diagnosed, prognosticated, treated, and/or ameliorated by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention include, but not limited to, the following families or class: Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic, Giardias, Helminthiasis, Leishmaniasis, Schistisoma, Theileriasis, Toxoplasmosis, Trypanosomiasis, and Trichomonas and Sporozoans (e.g., Plasmodium virax, Plasmodium falciparium, Plasmodium malariae and Plasmodium ovale). These parasites can cause a variety of diseases or symptoms, including, but not limited to: Scabies, Trombiculiasis, eye infections, intestinal disease (e.g., dysentery, giardiasis), liver disease, lung disease, opportunistic infections (e.g., AIDS related), malaria, pregnancy complications, and toxoplasmosis. polynucleotides or polypeptides, or agonists or antagonists of the invention, can be used to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate any of these symptoms or diseases. In specific embodiments, polynucleotides, polypeptides, or agonists or antagonists of the invention are used to detect, prevent, diagnose, treat, and/or ameliorate malaria.

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention of the present invention could either be by administering an effective amount of a polypeptide to the patient, or by removing cells from the patient, supplying the cells with a polynucleotide of the present invention, and returning the engineered cells to the patient (ex vivo therapy). Moreover, the polypeptide or polynucleotide of the present invention can be used as an antigen in a vaccine to raise an immune response against infectious disease.

Regeneration

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention can be used to differentiate, proliferate, and attract cells, leading to the regeneration of tissues. (See, Science 276:59-87 (1997)). The regeneration of tissues could be used to repair, replace, or protect tissue damaged by congenital defects, trauma (wounds, burns, incisions, or ulcers), age, disease (e.g. osteoporosis, osteocarthritis, periodontal disease, liver failure), surgery, including cosmetic plastic surgery, fibrosis, reperfusion injury, or systemic cytokine damage.

Tissues that could be regenerated using the present invention include organs (e.g., pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac), vasculature (including vascular and lymphatics), nervous, hematopoietic, and skeletal (bone, cartilage, tendon, and ligament) tissue. Preferably, regeneration occurs without or decreased scarring. Regeneration also may include angiogenesis.

Moreover, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may increase regeneration of tissues difficult to heal. For example, increased tendon/ligament regeneration would quicken recovery time after damage. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention could also be used prophylactically in an effort to avoid damage. Specific diseases that could be treated include of tendinitis, carpal tunnel syndrome, and other tendon or ligament defects. A further example of tissue regeneration of non-healing wounds includes pressure ulcers, ulcers associated with vascular insufficiency, surgical, and traumatic wounds.

Similarly, nerve and brain tissue could also be regenerated by using polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, to proliferate and differentiate nerve cells. Diseases that could be treated using this method include central and peripheral nervous system diseases, neuropathies, or mechanical and traumatic disorders (e.g., spinal cord disorders, head trauma, cerebrovascular disease, and stoke). Specifically, diseases associated with peripheral nerve injuries, peripheral neuropathy (e.g., resulting from chemotherapy or other medical therapies), localized neuropathies, and central nervous system diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome), could all be treated using the polynucleotides or polypeptides, as well as agonists or antagonists of the present invention.

Chemotaxis

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may have chemotaxis activity. A chemotaxic molecule attracts or mobilizes cells (e.g., monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells) to a particular site in the body, such as inflammation, infection, or site of hyperproliferation. The mobilized cells can then fight off and/or heal the particular trauma or abnormality.

Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may increase chemotaxic activity of particular cells. These chemotactic molecules can then be used to treat inflammation, infection, hyperproliferative disorders, or any immune system disorder by increasing the number of cells targeted to a particular location in the body. For example, chemotaxic molecules can be used to treat wounds and other trauma to tissues by attracting immune cells to the injured location. Chemotactic molecules of the present invention can also attract fibroblasts, which can be used to treat wounds.

It is also contemplated that polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may inhibit chemotactic activity. These molecules could also be used to treat disorders. Thus, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention could be used as an inhibitor of chemotaxis.

Binding Activity

A polypeptide of the present invention may be used to screen for molecules that bind to the polypeptide or for molecules to which the polypeptide binds. The binding of the polypeptide and the molecule may activate (agonist), increase, inhibit (antagonist), or decrease activity of the polypeptide or the molecule bound. Examples of such molecules include antibodies, oligonucleotides, proteins (e.g., receptors), or small molecules.

Preferably, the molecule is closely related to the natural ligand of the polypeptide, e.g., a fragment of the ligand, or a natural substrate, a ligand, a structural or functional mimetic. (See, Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991)). Similarly, the molecule can be closely related to the natural receptor to which the polypeptide binds, or at least, a fragment of the receptor capable of being bound by the polypeptide (e.g., active site). In either case, the molecule can be rationally designed using known techniques.

Preferably, the screening for these molecules involves producing appropriate cells which express the polypeptide. Preferred cells include cells from mammals, yeast, Drosophila, or E. coli. Cells expressing the polypeptide (or cell membrane containing the expressed polypeptide) are then preferably contacted with a test compound potentially containing the molecule to observe binding, stimulation, or inhibition of activity of either the polypeptide or the molecule.

The assay may simply test binding of a candidate compound to the polypeptide, wherein binding is detected by a label, or in an assay involving competition with a labeled competitor. Further, the assay may test whether the candidate compound results in a signal generated by binding to the polypeptide.

Alternatively, the assay can be carried out using cell-free preparations, polypeptide/molecule affixed to a solid support, chemical libraries, or natural product mixtures. The assay may also simply comprise the steps of mixing a candidate compound with a solution containing a polypeptide, measuring polypeptide/molecule activity or binding, and comparing the polypeptide/molecule activity or binding to a standard.

Preferably, an ELISA assay can measure polypeptide level or activity in a sample (e.g., biological sample) using a monoclonal or polyclonal antibody. The antibody can measure polypeptide level or activity by either binding, directly or indirectly, to the polypeptide or by competing with the polypeptide for a substrate.

Additionally, the receptor to which the polypeptide of the present invention binds can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting (Coligan, et al., Current Protocols in Immun., 1(2), Chapter 5, (1991)). For example, expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the polypeptides, for example, NIH3T3 cells which are known to contain multiple receptors for the FGF family proteins, and SC-3 cells, and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the polypeptides. Transfected cells which are grown on glass slides are exposed to the polypeptide of the present invention, after they have been labeled. The polypeptides can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase.

Following fixation and incubation, the slides are subjected to auto-radiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an iterative sub-pooling and re-screening process, eventually yielding a single clones that encodes the putative receptor.

As an alternative approach for receptor identification, the labeled polypeptides can be photoaffinity linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE analysis and exposed to X-ray film. The labeled complex containing the receptors of the polypeptides can be excised, resolved into peptide fragments, and subjected to protein microsequencing. The amino acid sequence obtained from microsequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the genes encoding the putative receptors.

Moreover, the techniques of gene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling (collectively referred to as “DNA shuffling”) may be employed to modulate the activities of the polypeptide of the present invention thereby effectively generating agonists and antagonists of the polypeptide of the present invention. See generally, U.S. Pat. Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458, and Patten, P. A., et al., Curr. Opinion Biotechnol. 8:724-33 (1997); Harayama, S. Trends Biotechnol. 16(2):76-82 (1998); Hansson, L. O., et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzo, M. M. and Blasco, R. Biotechniques 24(2):308-13 (1998); each of these patents and publications are hereby incorporated by reference). In one embodiment, alteration of polynucleotides and corresponding polypeptides may be achieved by DNA shuffling. DNA shuffling involves the assembly of two or more DNA segments into a desired molecule by homologous, or site-specific, recombination. In another embodiment, polynucleotides and corresponding polypeptides may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. In another embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of the polypeptide of the present invention may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules. In preferred embodiments, the heterologous molecules are family members. In further preferred embodiments, the heterologous molecule is a growth factor such as, for example, platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-1), transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), fibroblast growth factor (FGF), TGF-beta, bone morphogenetic protein (BMP)-2, BMP-4, BMP-5, BMP-6, BMP-7, activins A and B, decapentaplegic(dpp), 60A, OP-2, dorsalin, growth differentiation factors (GDFs), nodal, MIS, inhibin-alpha, TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta5, and glial-derived neurotrophic factor (GDNF).

Other preferred fragments are biologically active fragments of the polypeptide of the present invention. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.

Additionally, this invention provides a method of screening compounds to identify those which modulate the action of the polypeptide of the present invention. An example of such an assay comprises combining a mammalian fibroblast cell, a the polypeptide of the present invention, the compound to be screened and ³[H] thymidine under cell culture conditions where the fibroblast cell would normally proliferate. A control assay may be performed in the absence of the compound to be screened and compared to the amount of fibroblast proliferation in the presence of the compound to determine if the compound stimulates proliferation by determining the uptake of ³[H] thymidine in each case. The amount of fibroblast cell proliferation is measured by liquid scintillation chromatography which measures the incorporation of ³[H] thymidine. Both agonist and antagonist compounds may be identified by this procedure.

In another method, a mammalian cell or membrane preparation expressing a receptor for a polypeptide of the present invention is incubated with a labeled polypeptide of the present invention in the presence of the compound. The ability of the compound to enhance or block this interaction could then be measured. Alternatively, the response of a known second messenger system following interaction of a compound to be screened and the receptor is measured and the ability of the compound to bind to the receptor and elicit a second messenger response is measured to determine if the compound is a potential agonist or antagonist. Such second messenger systems include but are not limited to, cAMP guanylate cyclase, ion channels or phosphoinositide hydrolysis.

All of these above assays can be used as diagnostic or prognostic markers. The molecules discovered using these assays can be used to treat disease or to bring about a particular result in a patient (e.g., blood vessel growth) by activating or inhibiting the polypeptide/molecule. Moreover, the assays can discover agents which may inhibit or enhance the production of the polypeptides of the invention from suitably manipulated cells or tissues.

Therefore, the invention includes a method of identifying compounds which bind to a polypeptide of the invention comprising the steps of: (a) incubating a candidate binding compound with a polypeptide of the present invention; and (b) determining if binding has occurred. Moreover, the invention includes a method of identifying agonists/antagonists comprising the steps of: (a) incubating a candidate compound with a polypeptide of the present invention, (b) assaying a biological activity, and (b) determining if a biological activity of the polypeptide has been altered.

Targeted Delivery

In another embodiment, the invention provides a method of delivering compositions to targeted cells expressing a receptor for a polypeptide of the invention, or cells expressing a cell bound form of a polypeptide of the invention.

As discussed herein, polypeptides or antibodies of the invention may be associated with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/or covalent interactions. In one embodiment, the invention provides a method for the specific delivery of compositions of the invention to cells by administering polypeptides of the invention (including antibodies) that are associated with heterologous polypeptides or nucleic acids. In one example, the invention provides a method for delivering a therapeutic protein into the targeted cell. In another example, the invention provides a method for delivering a single stranded nucleic acid (e.g., antisense or ribozymes) or double stranded nucleic acid (e.g., DNA that can integrate into the cell's genome or replicate episomally and that can be transcribed) into the targeted cell.

In another embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention (e.g., polypeptides of the invention or antibodies of the invention) in association with toxins or cytotoxic prodrugs.

By “toxin” is meant compounds that bind and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell's death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. By “cytotoxic prodrug” is meant a non-toxic compound that is converted by an enzyme, normally present in the cell, into a cytotoxic compound. Cytotoxic prodrugs that may be used according to the methods of the invention include, but are not limited to, glutamyl derivatives of benzoic acid mustard alkylating agent, phosphate derivatives of etoposide or mitomycin C, cytosine arabinoside, daunorubisin, and phenoxyacetamide derivatives of doxorubicin.

Drug Screening

Further contemplated is the use of the polypeptides of the present invention, or the polynucleotides encoding these polypeptides, to screen for molecules which modify the activities of the polypeptides of the present invention. Such a method would include contacting the polypeptide of the present invention with a selected compound(s) suspected of having antagonist or agonist activity, and assaying the activity of these polypeptides following binding.

This invention is particularly useful for screening therapeutic compounds by using the polypeptides of the present invention, or binding fragments thereof, in any of a variety of drug screening techniques. The polypeptide or fragment employed in such a test may be affixed to a solid support, expressed on a cell surface, free in solution, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. One may measure, for example, the formulation of complexes between the agent being tested and a polypeptide of the present invention.

Thus, the present invention provides methods of screening for drugs or any other agents which affect activities mediated by the polypeptides of the present invention. These methods comprise contacting such an agent with a polypeptide of the present invention or a fragment thereof and assaying for the presence of a complex between the agent and the polypeptide or a fragment thereof, by methods well known in the art. In such a competitive binding assay, the agents to screen are typically labeled. Following incubation, free agent is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of a particular agent to bind to the polypeptides of the present invention.

Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to the polypeptides of the present invention, and is described in great detail in European Patent Application 84/03564, published on Sep. 13, 1984, which is incorporated herein by reference herein. Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The peptide test compounds are reacted with polypeptides of the present invention and washed. Bound polypeptides are then detected by methods well known in the art. Purified polypeptides are coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies may be used to capture the peptide and immobilize it on the solid support.

This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding polypeptides of the present invention specifically compete with a test compound for binding to the polypeptides or fragments thereof. In this manner, the antibodies are used to detect the presence of any peptide which shares one or more antigenic epitopes with a polypeptide of the invention.

Antisense And Ribozyme (Antagonists)

In specific embodiments, antagonists according to the present invention are nucleic acids corresponding to the sequences contained in SEQ ID NO:X, or the complementary strand thereof, and/or to cDNA sequences contained in cDNA ATCC Deposit No:Z identified for example, in Table 1A and/or 1B. In one embodiment, antisense sequence is generated internally, by the organism, in another embodiment, the antisense sequence is separately administered (see, for example, O'Connor, J., Neurochem. 56:560 (1991). Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Antisense technology can be used to control gene expression through antisense DNA or RNA, or through triple-helix formation. Antisense techniques are discussed for example, in Okano, J., Neurochem 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Triple helix formation is discussed in, for instance, Lee et al., Nucleic Acids Research 6:3073 (1979); Cooney et al., Science 241:456 (1988), and Dervan et al., Science 251:1300 (1991). The methods are based on binding of a polynucleotide to a complementary DNA or RNA.

For example, the use of c-myc and c-myb antisense RNA constructs to inhibit the growth of the non-lymphocytic leukemia cell line HL-60 and other cell lines was previously described. (Wickstrom et al. (1988); Anfossi et al. (1989)). These experiments were performed in vitro by incubating cells with the oligoribonucleotide. A similar procedure for in vivo use is described in WO 91/15580. Briefly, a pair of oligonucleotides for a given antisense RNA is produced as follows: A sequence complimentary to the first 15 bases of the open reading frame is flanked by an EcoR1 site on the 5 end and a HindIII site on the 3 end. Next, the pair of oligonucleotides is heated at 90° C. for one minute and then annealed in 2× ligation buffer (20 mM TRIS HCl pH 7.5, 10 mM MgCl2, 10MM dithiothreitol (DTT) and 0.2 mM ATP) and then ligated to the EcoR1/Hind III site of the retroviral vector PMV7 (WO 91/15580).

For example, the 5′ coding portion of a polynucleotide that encodes the polypeptide of the present invention may be used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription thereby preventing transcription and the production of the receptor. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into receptor polypeptide.

In one embodiment, the antisense nucleic acid of the invention is produced intracellularly by transcription from an exogenous sequence. For example, a vector or a portion thereof, is transcribed, producing an antisense nucleic acid (RNA) of the invention. Such a vector would contain a sequence encoding the antisense nucleic acid. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in vertebrate cells. Expression of the sequence encoding the polypeptide of the present invention or fragments thereof, can be by any promoter known in the art to act in vertebrate, preferably human cells. Such promoters can be inducible or constitutive. Such promoters include, but are not limited to, the SV40 early promoter region (Bernoist and Chambon, Nature 29:304-310 (1981), the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus (Yanamoto et al., Cell 22:787-797 (1980), the herpes thymidine promoter (Wagner et al., Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445 (1981), the regulatory sequences of the metallothionein gene (Brinster, et al., Nature 296:39-42 (1982)), etc.

The antisense nucleic acids of the invention comprise a sequence complementary to at least a portion of an RNA transcript of a gene of the present invention. However, absolute complementarity, although preferred, is not required. A sequence “complementary to at least a portion of an RNA,” referred to herein, means a sequence having sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the larger the hybridizing nucleic acid, the more base mismatches with a RNA it may contain and still form a stable duplex (or triplex as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.

Oligonucleotides that are complementary to the 5′ end of the message, e.g., the 5′ untranslated sequence up to and including the AUG initiation codon, should work most efficiently at inhibiting translation. However, sequences complementary to the 3′ untranslated sequences of mRNAs have been shown to be effective at inhibiting translation of mRNAs as well. See generally, Wagner, R., 1994, Nature 372:333-335. Thus, oligonucleotides complementary to either the 5′- or 3′-non-translated, non-coding regions of polynucleotide sequences described herein could be used in an antisense approach to inhibit translation of endogenous mRNA. Oligonucleotides complementary to the 5′ untranslated region of the mRNA should include the complement of the AUG start codon. Antisense oligonucleotides complementary to mRNA coding regions are less efficient inhibitors of translation but could be used in accordance with the invention. Whether designed to hybridize to the 5′-, 3′- or coding region of mRNA of the present invention, antisense nucleic acids should be at least six nucleotides in length, and are preferably oligonucleotides ranging from 6 to about 50 nucleotides in length. In specific aspects the oligonucleotide is at least 10 nucleotides, at least 17 nucleotides, at least 25 nucleotides or at least 50 nucleotides.

The polynucleotides of the invention can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, hybridization, etc. The oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652; PCT Publication No. WO88/09810, published Dec. 15, 1988) or the blood-brain barrier (see, e.g., PCT Publication No. WO89/10134, published Apr. 25, 1988), hybridization-triggered cleavage agents. (See, e.g., Krol et al., 1988, BioTechniques 6:958-976) or intercalating agents. (See, e.g., Zon, 1988, Pharm. Res. 5:539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.

The antisense oligonucleotide may comprise at least one modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.

The antisense oligonucleotide may also comprise at least one modified sugar moiety selected from the group including, but not limited to, arabinose, 2-fluoroarabinose, xylulose, and hexose.

In yet another embodiment, the antisense oligonucleotide comprises at least one modified phosphate backbone selected from the group including, but not limited to, a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.

In yet another embodiment, the antisense oligonucleotide is an a-anomeric oligonucleotide. An a-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual b-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a 2′-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330).

Polynucleotides of the invention may be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc.

While antisense nucleotides complementary to the coding region sequence could be used, those complementary to the transcribed untranslated region are most preferred.

Potential antagonists according to the invention also include catalytic RNA, or a ribozyme (See, e.g., PCT International Publication WO 90/11364, published Oct. 4, 1990; Sarver et al, Science 247:1222-1225 (1990). While ribozymes that cleave mRNA at site specific recognition sequences can be used to destroy mRNAs, the use of hammerhead ribozymes is preferred. Hammerhead ribozymes cleave mRNAs at locations dictated by flanling regions that form complementary base pairs with the target mRNA. The sole requirement is that the target mRNA have the following sequence of two bases: 5′-UG-3′. The construction and production of hammerhead ribozymes is well known in the art and is described more fully in Haseloff and Gerlach, Nature 334:585-591 (1988). There are numerous potential hammerhead ribozyme cleavage sites within the nucleotide sequence of SEQ ID NO:X. Preferably, the ribozyme is engineered so that the cleavage recognition site is located near the 5′ end of the mRNA; i.e., to increase efficiency and minimize the intracellular accumulation of non-functional mRNA transcripts.

As in the antisense approach, the ribozymes of the invention can be composed of modified oligonucleotides (e.g., for improved stability, targeting, etc.) and should be delivered to cells which express in vivo. DNA constructs encoding the ribozyme may be introduced into the cell in the same manner as described above for the introduction of antisense encoding DNA. A preferred method of delivery involves using a DNA construct “encoding” the ribozyme under the control of a strong constitutive promoter, such as, for example, pol III or pol II promoter, so that transfected cells will produce sufficient quantities of the ribozyme to destroy endogenous messages and inhibit translation. Since ribozymes unlike antisense molecules, are catalytic, a lower intracellular concentration is required for efficiency.

Antagonist/agonist compounds may be employed to inhibit the cell growth and proliferation effects of the polypeptides of the present invention on neoplastic cells and tissues, i.e. stimulation of angiogenesis of tumors, and, therefore, retard or prevent abnormal cellular growth and proliferation, for example, in tumor formation or growth.

The antagonist/agonist may also be employed to prevent hyper-vascular diseases, and prevent the proliferation of epithelial lens cells after extracapsular cataract surgery. Prevention of the mitogenic activity of the polypeptides of the present invention may also be desirous in cases such as restenosis after balloon angioplasty.

The antagonist/agonist may also be employed to prevent the growth of scar tissue during wound healing.

The antagonist/agonist may also be employed to treat the diseases described herein.

Thus, the invention provides a method of treating disorders or diseases, including but not limited to the disorders or diseases listed throughout this application, associated with overexpression of a polynucleotide of the present invention by administering to a patient (a) an antisense molecule directed to the polynucleotide of the present invention, and/or (b) a ribozyme directed to the polynucleotide of the present invention.

Binding Peptides and Other Molecules

The invention also encompasses screening methods for identifying polypeptides and nonpolypeptides that bind polypeptides of the invention, and the binding molecules identified thereby. These binding molecules are useful, for example, as agonists and antagonists of the polypeptides of the invention. Such agonists and antagonists can be used, in accordance with the invention, in the therapeutic embodiments described in detail, below.

This method comprises the steps of:

-   -   contacting polypeptides of the invention with a plurality of         molecules; and     -   identifying a molecule that binds the polypeptides of the         invention.

The step of contacting the polypeptides of the invention with the plurality of molecules may be effected in a number of ways. For example, one may contemplate immobilizing the polypeptides on a solid support and bringing a solution of the plurality of molecules in contact with the immobilized polypeptides. Such a procedure would be akin to an affinity chromatographic process, with the affinity matrix being comprised of the immobilized polypeptides of the invention. The molecules having a selective affinity for the polypeptides can then be purified by affinity selection. The nature of the solid support, process for attachment of the polypeptides to the solid support, solvent, and conditions of the affinity isolation or selection are largely conventional and well known to those of ordinary skill in the art.

Alternatively, one may also separate a plurality of polypeptides into substantially separate fractions comprising a subset of or individual polypeptides. For instance, one can separate the plurality of polypeptides by gel electrophoresis, column chromatography, or like method known to those of ordinary skill for the separation of polypeptides. The individual polypeptides can also be produced by a transformed host cell in such a way as to be expressed on or about its outer surface (e.g., a recombinant phage). Individual isolates can then be “probed” by the polypeptides of the invention, optionally in the presence of an inducer should one be required for expression, to determine if any selective affinity interaction takes place between the polypeptides and the individual clone. Prior to contacting the polypeptides with each fraction comprising individual polypeptides, the polypeptides could first be transferred to a solid support for additional convenience. Such a solid support may simply be a piece of filter membrane, such as one made of nitrocellulose or nylon. In this manner, positive clones could be identified from a collection of transformed host cells of an expression library, which harbor a DNA construct encoding a polypeptide having a selective affinity for polypeptides of the invention. Furthermore, the amino acid sequence of the polypeptide having a selective affinity for the polypeptides of the invention can be determined directly by conventional means or the coding sequence of the DNA encoding the polypeptide can frequently be determined more conveniently. The primary sequence can then be deduced from the corresponding DNA sequence. If the amino acid sequence is to be determined from the polypeptide itself, one may use microsequencing techniques. The sequencing technique may include mass spectroscopy.

In certain situations, it may be desirable to wash away any unbound polypeptides from a mixture of the polypeptides of the invention and the plurality of polypeptides prior to attempting to determine or to detect the presence of a selective affinity interaction. Such a wash step may be particularly desirable when the polypeptides of the invention or the plurality of polypeptides are bound to a solid support.

The plurality of molecules provided according to this method may be provided by way of diversity libraries, such as random or combinatorial peptide or nonpeptide libraries which can be screened for molecules that specifically bind polypeptides of the invention. Many libraries are known in the art that can be used, e.g., chemically synthesized libraries, recombinant (e.g., phage display libraries), and in vitro translation-based libraries. Examples of chemically synthesized libraries are described in Fodor et al., 1991, Science 251:767-773; Houghten et al., 1991, Nature 354:84-86; Lam et al., 1991, Nature 354:82-84; Medynski, 1994, Bio/Technology 12:709-710; Gallop et al., 1994, J. Medicinal Chemistry 37(9):1233-1251; Ohlmeyer et al., 1993, Proc. Natl. Acad. Sci. USA 90:10922-10926; Erb et al., 1994, Proc. Natl. Acad. Sci. USA 91:11422-11426; Houghten et al., 1992, Biotechniques 13:412; Jayawickreme et al., 1994, Proc. Natl. Acad. Sci. USA 91:1614-1618; Salmon et al., 1993, Proc. Natl. Acad. Sci. USA 90:11708-11712; PCT Publication No. WO 93/20242; and Brenner and Lerner, 1992, Proc. Natl. Acad. Sci. USA 89:5381-5383.

Examples of phage display libraries are described in Scott and Smith, 1990, Science 249:386-390; Devlin et al., 1990, Science, 249:404-406; Christian, R. B., et al., 1992, J. Mol. Biol. 227:711-718); Lenstra, 1992, J. Immunol. Meth. 152:149-157; Kay et al., 1993′, Gene 128:59-65; and PCT Publication No. WO 94/18318 dated Aug. 18, 1994.

In vitro translation-based libraries include but are not limited to those described in PCT Publication No. WO 91/05058 dated Apr. 18, 1991; and Mattheakis et al., 1994, Proc. Natl. Acad. Sci. USA 91:9022-9026.

By way of examples of nonpeptide libraries, a benzodiazepine library (see e.g., Bunin et al., 1994, Proc. Natl. Acad. Sci. USA 91:4708-4712) can be adapted for use. Peptoid libraries (Simon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367-9371) can also be used. Another example of a library that can be used, in which the amide functionalities in peptides have been permethylated to generate a chemically transformed combinatorial library, is described by Ostresh et al. (1994, Proc. Natl. Acad. Sci. USA 91:11138-11142).

The variety of non-peptide libraries that are useful in the present invention is great. For example, Ecker and Crooke, 1995, Bio/Technology 13:351-360 list benzodiazepines, hydantoins, piperazinediones, biphenyls, sugar analogs, beta-mercaptoketones, arylacetic acids, acylpiperidines, benzopyrans, cubanes, xanthines, aminimides, and oxazolones as among the chemical species that form the basis of various libraries.

Non-peptide libraries can be classified broadly into two types: decorated monomers and oligomers. Decorated monomer libraries employ a relatively simple scaffold structure upon which a variety functional groups is added. Often the scaffold will be a molecule with a known useful pharmacological activity. For example, the scaffold might be the benzodiazepine structure.

Non-peptide oligomer libraries utilize a large number of monomers that are assembled together in ways that create new shapes that depend on the order of the monomers. Among the monomer units that have been used are carbamates, pyrrolinones, and morpholinos. Peptoids, peptide-like oligomers in which the side chain is attached to the alpha amino group rather than the alpha carbon, form the basis of another version of non-peptide oligomer libraries. The first non-peptide oligomer libraries utilized a single type of monomer and thus contained a repeating backbone. Recent libraries have utilized more than one monomer, giving the libraries added flexibility.

Screening the libraries can be accomplished by any of a variety of commonly known methods. See, e.g., the following references, which disclose screening of peptide libraries: Parmley and Smith, 1989, Adv. Exp. Med. Biol. 251:215-218; Scott and Smith, 1990, Science 249:386-390; Fowlkes et al., 1992; BioTechniques 13:422-427; Oldenburg et al., 1992, Proc. Natl. Acad. Sci. USA 89:5393-5397; Yu et al., 1994, Cell 76:933-945; Staudt et al., 1988, Science 241:577-580; Bock et al., 1992, Nature 355:564-566; Tuerk et al., 1992, Proc. Natl. Acad. Sci. USA 89:6988-6992; Ellington et al., 1992, Nature 355:850-852; U.S. Pat. No. 5,096,815, U.S. Pat. No. 5,223,409, and U.S. Pat. No. 5,198,346, all to Ladner et al.; Rebar and Pabo, 1993, Science 263:671-673; and CT Publication No. WO 94/18318.

In a specific embodiment, screening to identify a molecule that binds polypeptides of the invention can be carried out by contacting the library members with polypeptides of the invention immobilized on a solid phase and harvesting those library members that bind to the polypeptides of the invention. Examples of such screening methods, termed “panning” techniques are described by way of example in Parmley and Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTechniques 13:422-427; PCT Publication No. WO 94/18318; and in references cited herein.

In another embodiment, the two-hybrid system for selecting interacting proteins in yeast (Fields and Song, 1989, Nature 340:245-246; Chien et al., 1991, Proc. Natl. Acad. Sci. USA 88:9578-9582) can be used to identify molecules that specifically bind to polypeptides of the invention.

Where the binding molecule is a polypeptide, the polypeptide can be conveniently selected from any peptide library, including random peptide libraries, combinatorial peptide libraries, or biased peptide libraries. The term “biased” is used herein to mean that the method of generating the library is manipulated so as to restrict one or more parameters that govern the diversity of the resulting collection of molecules, in this case peptides.

Thus, a truly random peptide library would generate a collection of peptides in which the probability of finding a particular amino acid at a given position of the peptide is the same for all 20 amino acids. A bias can be introduced into the library, however, by specifying, for example, that a lysine occur every fifth amino acid or that positions 4, 8, and 9 of a decapeptide library be fixed to include only arginine. Clearly, many types of biases can be contemplated, and the present invention is not restricted to any particular bias. Furthermore, the present invention contemplates specific types of peptide libraries, such as phage displayed peptide libraries and those that utilize a DNA construct comprising a lambda phage vector with a DNA insert.

As mentioned above, in the case of a binding molecule that is a polypeptide, the polypeptide may have about 6 to less than about 60 amino acid residues, preferably about 6 to about 10 amino acid residues, and most preferably, about 6 to about 22 amino acids. In another embodiment, a binding polypeptide has in the range of 15-100 amino acids, or 20-50 amino acids.

The selected binding polypeptide can be obtained by chemical synthesis or recombinant expression.

Other Activities

A polypeptide, polynucleotide, agonist, or antagonist of the present invention, as a result of the ability to stimulate vascular endothelial cell growth, may be employed in treatment for stimulating re-vascularization of ischemic tissues due to various disease conditions such as thrombosis, arteriosclerosis, and other cardiovascular conditions. The polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed to stimulate angiogenesis and limb regeneration, as discussed above.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for treating wounds due to injuries, burns, post-operative tissue repair, and ulcers since they are mitogenic to various cells of different origins, such as fibroblast cells and skeletal muscle cells, and therefore, facilitate the repair or replacement of damaged or diseased tissue.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed stimulate neuronal growth and to treat and prevent neuronal damage which occurs in certain neuronal disorders or neuro-degenerative conditions such as Alzheimer's disease, Parkinson's disease, and AIDS-related complex. A polypeptide, polynucleotide, agonist, or antagonist of the present invention may have the ability to stimulate chondrocyte growth, therefore, they may be employed to enhance bone and periodontal regeneration and aid in tissue transplants or bone grafts.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may be also be employed to prevent skin aging due to sunburn by stimulating keratinocyte growth.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for preventing hair loss, since FGF family members activate hair-forming cells and promotes melanocyte growth. Along the same lines, a polypeptide, polynucleotide, agonist, or antagonist of the present invention may be employed to stimulate growth and differentiation of hematopoietic cells and bone marrow cells when used in combination with other cytokines.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed to maintain organs before transplantation or for supporting cell culture of primary tissues. A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for inducing tissue of mesodermal origin to differentiate in early embryos.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also increase or decrease the differentiation or proliferation of embryonic stem cells, besides, as discussed above, hematopoietic lineage.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be used to modulate mammalian characteristics, such as body height, weight, hair color, eye color, skin, percentage of adipose tissue, pigmentation, size, and shape (e.g., cosmetic surgery). Similarly, a polypeptide, polynucleotide, agonist, or antagonist of the present invention may be used to modulate mammalian metabolism affecting catabolism, anabolism, processing, utilization, and storage of energy.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may be used to change a mammal's mental state or physical state by influencing biorhythms, caricadic rhythms, depression (including depressive disorders), tendency for violence, tolerance for pain, reproductive capabilities (preferably by Activin or Inhibin-like activity), hormonal or endocrine levels, appetite, libido, memory, stress, or other cognitive qualities.

A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be used as a food additive or preservative, such as to increase or decrease storage capabilities, fat content, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional components.

The above-recited applications have uses in a wide variety of hosts. Such hosts include, but are not limited to, human, murine, rabbit, goat, guinea pig, camel, horse, mouse, rat, hamster, pig, micro-pig, chicken, goat, cow, sheep, dog, cat, non-human primate, and human. In specific embodiments, the host is a mouse, rabbit, goat, guinea pig, chicken, rat, hamster, pig, sheep, dog or cat. In preferred embodiments, the host is a mammal. In most preferred embodiments, the host is a human.

OTHER PREFERRED EMBODIMENTS

Other preferred embodiments of the claimed invention include an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 50 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1B or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in ATCC Deposit No:Z.

Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of the portion of SEQ ID NO:X as defined in column 5, “ORF (From-To)”, in Table 1B.1.

Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of the portion of SEQ ID NO:X as defined in columns 8 and 9, “NT From” and “NT To” respectively, in Table 2.

Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 150 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in ATCC Deposit No:Z.

Further preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 500 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in ATCC Deposit No:Z.

A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the nucleotide sequence of the portion of SEQ ID NO:X defined in column 5, “ORF (From-To)”, in Table 1B.1.

A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the nucleotide sequence of the portion of SEQ ID NO:X defined in columns 8 and 9, “NT From” and “NT To”, respectively, in Table 2.

A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto, the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in ATCC Deposit No:Z, wherein said nucleic acid molecule which hybridizes does not hybridize under stringent hybridization conditions to a nucleic acid molecule having a nucleotide sequence consisting of only A residues or of only T residues.

Also preferred is a composition of matter comprising a DNA molecule which comprises the cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least 50 contiguous nucleotides of the cDNA sequence contained in ATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule, wherein said sequence of at least 50 contiguous nucleotides is included in the nucleotide sequence of an open reading frame sequence encoded by cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least 150 contiguous nucleotides in the nucleotide sequence encoded by cDNA contained in ATCC Deposit No:Z.

A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least 500 contiguous nucleotides in the nucleotide sequence encoded by cDNA contained in ATCC Deposit No:Z.

A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence encoded by cDNA contained in ATCC Deposit No:Z.

A further preferred embodiment is a method for detecting in a biological sample a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence encoded by cDNA contained in ATCC Deposit No:Z; which method comprises a step of comparing a nucleotide sequence of at least one nucleic acid molecule in said sample with a sequence selected from said group and determining whether the sequence of said nucleic acid molecule in said sample is at least 95% identical to said selected sequence.

Also preferred is the above method wherein said step of comparing sequences comprises determining the extent of nucleic acid hybridization between nucleic acid molecules in said sample and a nucleic acid molecule comprising said sequence selected from said group. Similarly, also preferred is the above method wherein said step of comparing sequences is performed by comparing the nucleotide sequence determined from a nucleic acid molecule in said sample with said sequence selected from said group. The nucleic acid molecules can comprise DNA molecules or RNA molecules.

A further preferred embodiment is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting nucleic acid molecules in said sample, if any, comprising a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence of the cDNA contained in ATCC Deposit No:Z.

The method for identifying the species, tissue or cell type of a biological sample can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.

Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto; or the cDNA contained in ATCC Deposit No:Z which encodes a protein, wherein the method comprises a step of detecting in a biological sample obtained from said subject nucleic acid molecules, if any, comprising a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence of cDNA contained in ATCC Deposit No:Z.

The method for diagnosing a pathological condition can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.

Also preferred is a composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X or the complementary strand thereto; the nucleotide sequence as defined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence encoded by cDNA contained in ATCC Deposit No:Z. The nucleic acid molecules can comprise DNA molecules or RNA molecules.

Also preferred is a composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a DNA microarray or “chip” of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 100, 150, 200, 250, 300, 500, 1000, 2000, 3000, or 4000 nucleotide sequences, wherein at least one sequence in said DNA microarray or “chip” is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1A and/or 1B; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA “Clone ID” in Table 1A and/or 1B.

Also preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in ATCC Deposit No:Z.

Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in ATCC Deposit No:Z.

Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the complete amino acid sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in ATCC Deposit No:Z.

Further preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the complete amino acid sequence of a polypeptide encoded by contained in ATCC Deposit No:Z

Also preferred is a polypeptide wherein said sequence of contiguous amino acids is included in the amino acid sequence of a portion of said polypeptide encoded by cDNA contained in ATCC Deposit No:Z; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or the polypeptide sequence of SEQ ID NO:Y.

Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of a polypeptide encoded by cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the amino acid sequence of a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Further preferred is an isolated antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Further preferred is a method for detecting in a biological sample a polypeptide comprising an amino acid sequence which is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z; which method comprises a step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group and determining whether the sequence of said polypeptide molecule in said sample is at least 90% identical to said sequence of at least 10 contiguous amino acids.

Also preferred is the above method wherein said step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group comprises determining the extent of specific binding of polypeptides in said sample to an antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Also preferred is the above method wherein said step of comparing sequences is performed by comparing the amino acid sequence determined from a polypeptide molecule in said sample with said sequence selected from said group.

Also preferred is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting polypeptide molecules in said sample, if any, comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Also preferred is the above method for identifying the species, tissue or cell type of a biological sample, which method comprises a step of detecting polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the above group.

Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a nucleic acid sequence identified in Table 1A, 1B or Table 2 encoding a polypeptide, which method comprises a step of detecting in a biological sample obtained from said subject polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

In any of these methods, the step of detecting said polypeptide molecules includes using an antibody.

Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a nucleotide sequence encoding a polypeptide wherein said polypeptide comprises an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule, wherein said nucleotide sequence encoding a polypeptide has been optimized for expression of said polypeptide in a prokaryotic host.

Also preferred is a polypeptide molecule, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Further preferred is a method of making a recombinant vector comprising inserting any of the above isolated nucleic acid molecule into a vector. Also preferred is the recombinant vector produced by this method. Also preferred is a method of making a recombinant host cell comprising introducing the vector into a host cell, as well as the recombinant host cell produced by this method.

Also preferred is a method of making an isolated polypeptide comprising culturing this recombinant host cell under conditions such that said polypeptide is expressed and recovering said polypeptide. Also preferred is this method of making an isolated polypeptide, wherein said recombinant host cell is a eukaryotic cell and said polypeptide is a human protein comprising an amino acid sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z. The isolated polypeptide produced by this method is also preferred.

Also preferred is a method of treatment of an individual in need of an increased level of a protein activity, which method comprises administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide, polynucleotide, immunogenic fragment or analogue thereof, binding agent, antibody, or antigen binding fragment of the claimed invention effective to increase the level of said protein activity in said individual.

Also preferred is a method of treatment of an individual in need of a decreased level of a protein activity, which method comprised administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide, polynucleotide, immunogenic fragment or analogue thereof, binding agent, antibody, or antigen binding fragment of the claimed invention effective to decrease the level of said protein activity in said individual.

Also preferred is a method of treatment of an individual in need of a specific delivery of toxic compositions to diseased cells (e.g., tumors, leukemias or lymphomas), which method comprises administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide of the invention, including, but not limited to a binding agent, or antibody of the claimed invention that are associated with toxin or cytotoxic prodrugs.

Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting.

Description of Table 6

Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application. These deposits were made in addition to those described in the Table 1A. TABLE 6 ATCC Deposits Deposit Date ATCC Designation Number LP01, LP02, LP03, LP04, May-20-97 209059, 209060, 209061, LP05, LP06, LP07, LP08, 209062, 209063, 209064, LP09, LP10, LP11, 209065, 209066, 209067, 209068, 209069 LP12 Jan-12-98 209579 LP13 Jan-12-98 209578 LP14 Jul-16-98 203067 LP15 Jul-16-98 203068 LP16 Feb-1-99 203609 LP17 Feb-1-99 203610 LP20 Nov-17-98 203485 LP21 Jun-18-99 PTA-252 LP22 Jun-18-99 PTA-253 LP23 Dec-22-99 PTA-1081

EXAMPLES Example 1 Isolation of a Selected cDNA Clone from the Deposited Sample

Each ATCC Deposit No:Z is contained in a plasmid vector. Table 7 identifies the vectors used to construct the cDNA library from which each clone was isolated. In many cases, the vector used to construct the library is a phage vector from which a plasmid has been excised. The following correlates the related plasmid for each phage vector used in constructing the cDNA library. For example, where a particular clone is identified in Table 7 as being isolated in the vector “Lambda Zap,” the corresponding deposited clone is in “pBluescript.” Vector Used to Corresponding Construct Library Deposited Plasmid Lambda Zap pBluescript (pBS) Uni-Zap XR pBluescript (pBS) Zap Express pBK lafmid BA plafmid BA pSport1 pSport1 pCMVSport 2.0 pCMVSport 2.0 pCMVSport 3.0 pCMVSport 3.0 pCR ® 2.1 pCR ® 2.1

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Both can be transformed into E. coli strain XL-1 Blue, also available from Stratagene. pBS comes in 4 forms SK+, SK−, KS+ and KS. The S and K refers to the orientation of the polylinker to the T7 and T3 primer sequences which flank the polylinker region (“S” is for SacI and “K” is for KpnI which are the first sites on each respective end of the linker). “+” or “−” refer to the orientation of the f1 origin of replication (“ori”), such that in one orientation, single stranded rescue initiated from the f1 ori generates sense strand DNA and in the other, antisense.

Vectors pSport1, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. (See, for instance, Gruber, C. E., et al., Focus 15:59 (1993)). Vector lafmid BA (Bento Soares, Columbia University, NY) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR®2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. (See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991)). Preferably, a polynucleotide of the present invention does not comprise the phage vector sequences identified for the particular clone in Table 7, as well as the corresponding plasmid vector sequences designated above.

The deposited material in the sample assigned the ATCC Deposit Number cited by reference to Table 1A, Table 2, Table 6 and Table 7 for any given cDNA clone also may contain one or more additional plasmids, each comprising a cDNA clone different from that given clone. Thus, deposits sharing the same ATCC Deposit Number contain at least a plasmid for each ATCC Deposit No:Z. TABLE 7 ATCC Libraries owned by Catalog Catalog Description Vector Deposit HUKA HUKB HUKC HUKD Human Uterine Cancer Lambda ZAP II LP01 HUKE HUKF HUKG HCNA HCNB Human Colon Lambda Zap II LP01 HFFA Human Fetal Brain, random Lambda Zap II LP01 primed HTWA Resting T-Cell Lambda ZAP II LP01 HBQA Early Stage Human Brain, Lambda ZAP II LP01 random primed HLMB HLMF HLMG HLMH breast lymph node CDNA Lambda ZAP II LP01 HLMI HLMJ HLMM HLMN library HCQA HCQB human colon cancer Lamda ZAP II LP01 HMEA HMEC HMED HMEE Human Microvascular Lambda ZAP II LP01 HMEF HMEG HMEI HMEJ Endothelial Cells, fract. A HMEK HMEL HUSA HUSC Human Umbilical Vein Lambda ZAP II LP01 Endothelial Cells, fract. A HLQA HLQB Hepatocellular Tumor Lambda ZAP II LP01 HHGA HHGB HHGC HHGD Hemangiopericytoma Lambda ZAP II LP01 HSDM Human Striatum Depression, re- Lambda ZAP II LP01 rescue HUSH H Umbilical Vein Endothelial Lambda ZAP II LP01 Cells, frac A, re-excision HSGS Salivary gland, subtracted Lambda ZAP II LP01 HFXA HFXB HFXC HFXD Brain frontal cortex Lambda ZAP II LP01 HFXE HFXF HFXG HFXH HPQA HPQB HPQC PERM TF274 Lambda ZAP II LP01 HFXJ HFXK Brain Frontal Cortex, re-excision Lambda ZAP II LP01 HCWA HCWB HCWC HCWD CD34 positive cells (Cord ZAP Express LP02 HCWE HCWF HCWG HCWH Blood) HCWI HCWJ HCWK HCUA HCUB HCUC CD34 depleted Buffy Coat ZAP Express LP02 (Cord Blood) HRSM A-14 cell line ZAP Express LP02 HRSA A1-CELL LINE ZAP Express LP02 HCUD HCUE HCUF HCUG CD34 depleted Buffy Coat ZAP Express LP02 HCUH HCUI (Cord Blood), re-excision HBXE HBXF HBXG H. Whole Brain #2, re-excision ZAP Express LP02 HRLM L8 cell line ZAP Express LP02 HBXA HBXB HBXC HBXD Human Whole Brain #2 - Oligo ZAP Express LP02 dT >1.5 Kb HUDA HUDB HUDC Testes ZAP Express LP02 HHTM HHTN HHTO H. hypothalamus, frac A; re- ZAP Express LP02 excision HHTL H. hypothalamus, frac A ZAP Express LP02 HASA HASD Human Adult Spleen Uni-ZAP XR LP03 HFKC HFKD HFKE HFKF Human Fetal Kidney Uni-ZAP XR LP03 HFKG HE8A HE8B HE8C HE8D Human 8 Week Whole Embryo Uni-ZAP XR LP03 HE8E HE8F HE8M HE8N HGBA HGBD HGBE HGBF Human Gall Bladder Uni-ZAP XR LP03 HGBG HGBH HGBI HLHA HLHB HLHC HLHD Human Fetal Lung III Uni-ZAP XR LP03 HLHE HLHF HLHG HLHH HLHQ HPMA HPMB HPMC HPMD Human Placenta Uni-ZAP XR LP03 HPME HPMF HPMG HPMH HPRA HPRB HPRC HPRD Human Prostate Uni-ZAP XR LP03 HSIA HSIC HSID HSIE Human Adult Small Intestine Uni-ZAP XR LP03 HTEA HTEB HTEC HTED Human Testes Uni-ZAP XR LP03 HTEE HTEF HTEG HTEH HTEI HTEJ HTEK HTPA HTPB HTPC HTPD Human Pancreas Tumor Uni-ZAP XR LP03 HTPE HTTA HTTB HTTC HTTD Human Testes Tumor Uni-ZAP XR LP03 HTTE HTTF HAPA HAPB HAPC HAPM Human Adult Pulmonary Uni-ZAP XR LP03 HETA HETB HETC HETD Human Endometrial Tumor Uni-ZAP XR LP03 HETE HETF HETG HETH HETI HHFB HHFC HHFD HHFE Human Fetal Heart Uni-ZAP XR LP03 HHFF HHFG HHFH HHFI HHPB HHPC HHPD HHPE Human Hippocampus Uni-ZAP XR LP03 HHPF HHPG HHPH HCE1 HCE2 HCE3 HCE4 Human Cerebellum Uni-ZAP XR LP03 HCE5 HCEB HCEC HCED HCEE HCEF HCEG HUVB HUVC HUVD HUVE Human Umbilical Vein, Endo. Uni-ZAP XR LP03 remake HSTA HSTB HSTC HSTD Human Skin Tumor Uni-ZAP XR LP03 HTAA HTAB HTAC HTAD Human Activated T-Cells Uni-ZAP XR LP03 HTAE HFEA HFEB HFEC Human Fetal Epithelium (Skin) Uni-ZAP XR LP03 HJPA HJPB HJPC HJPD HUMAN JURKAT Uni-ZAP XR LP03 MEMBRANE BOUND POLYSOMES HESA Human epithelioid sarcoma Uni-Zap XR LP03 HLTA HLTB HLTC HLTD Human T-Cell Lymphoma Uni-ZAP XR LP03 HLTE HLTF HFTA HFTB HFTC HFTD Human Fetal Dura Mater Uni-ZAP XR LP03 HRDA HRDB HRDC HRDD Human Rhabdomyosarcoma Uni-ZAP XR LP03 HRDE HRDF HCAA HCAB HCAC Cem cells cyclohexamide treated Uni-ZAP XR LP03 HRGA HRGB HRGC HRGD Raji Cells, cyclohexamide Uni-ZAP XR LP03 treated HSUA HSUB HSUC HSUM Supt Cells, cyclohexamide Uni-ZAP XR LP03 treated HT4A HT4C HT4D Activated T-Cells, 12 hrs. Uni-ZAP XR LP03 HE9A HE9B HB9C HE9D Nine Week Old Early Stage Uni-ZAP XR LP03 HE9E HE9F HE9G HE9H Human HE9M HE9N HATA HATB HATC HATD Human Adrenal Gland Tumor Uni-ZAP XR LP03 HATE HT5A Activated T-Cells, 24 hrs. Uni-ZAP XR LP03 HFGA HFGM Human Fetal Brain Uni-ZAP XR LP03 HNEA HNEB HNEC HNED Human Neutrophil Uni-ZAP XR LP03 HNEE HBGB HBGD Human Primary Breast Cancer Uni-ZAP XR LP03 HBNA HBNB Human Normal Breast Uni-ZAP XR LP03 HCAS Cem Cells, cyclohexamide Uni-ZAP XR LP03 treated, subtra HHPS Human Hippocampus, pBS LP03 subtracted HKCS HKCU Human Colon Cancer, pBS LP03 subtracted HRGS Raji cells, cyclohexamide pBS LP03 treated, subtracted HSUT Supt cells, cyclohexamide pBS LP03 treated, differentially expressed HT4S Activated T-Cells, 12 hrs, Uni-ZAP XR LP03 subtracted HCDA HCDB HCDC HCDD Human Chondrosarcoma Uni-ZAP XR LP03 HCDE HOAA HOAB HOAC Human Osteosarcoma Uni-ZAP XR LP03 HTLA HTLB HTLC HTLD Human adult testis, large inserts Uni-ZAP XR LP03 HTLE HTLF HLMA HLMC HLMD Breast Lymph node cDNA Uni-ZAP XR LP03 library H6EA H6EB H6EC HL-60, PMA 4H Uni-ZAP XR LP03 HTXA HTXB HTXC HTXD Activated T-Cell Uni-ZAP XR LP03 HTXE HTXF HTXG HTXH (12 hs)/Thiouridine labelledEco HNFA HNFB HNFC HNFD Human Neutrophil, Activated Uni-ZAP XR LP03 HNFE HNFF HNFG HNFH HNFJ HTOB HTOC HUMAN TONSILS, Uni-ZAP XR LP03 FRACTION 2 HMGB Human OB MG63 control Uni-ZAP XR LP03 fraction I HOPB Human OB HOS control fraction I Uni-ZAP XR LP03 HORB Human OB HOS treated (10 nM Uni-ZAP XR LP03 E2) fraction I HSVA HSVB HSVC Human Chronic Synovitis Uni-ZAP XR LP03 HROA HUMAN STOMACH Uni-ZAP XR LP03 HBJA HBJB HBJC HBJD HBJE HUMAN B CELL Uni-ZAP XR LP03 HBJF HBJG HBJH HBJI HBJJ LYMPHOMA HBJK HCRA HCRB HCRC human corpus colosum Uni-ZAP XR LP03 HODA HODB HODC HODD human ovarian cancer Uni-ZAP XR LP03 HDSA Dermatofibrosarcoma Uni-ZAP XR LP03 Protuberance HMWA HMWB HMWC Bone Marrow Cell Line Uni-ZAP XR LP03 HMWD HMWE HMWF (RS4; 11) HMWG HMWH HMWI HMWJ HSOA stomach cancer (human) Uni-ZAP XR LP03 HERA SKIN Uni-ZAP XR LP03 HMDA Brain-medulloblastoma Uni-ZAP XR LP03 HGLA HGLB HGLD Glioblastoma Uni-ZAP XR LP03 HEAA H. Atrophic Endometrium Uni-ZAP XR LP03 HBCA HBCB H. Lymph node breast Cancer Uni-ZAP XR LP03 HPWT Human Prostate BPH, re- Uni-ZAP XR LP03 excision HFVG HFVH HFVI Fetal Liver, subtraction II pBS LP03 HNFI Human Neutrophils, Activated, pBS LP03 re-excision HBMB HBMC HBMD Human Bone Marrow, re- pBS LP03 excision HKML HKMM HKMN H. Kidney Medulla, re-excision pBS LP03 HKIX HKIY H. Kidney Cortex, subtracted pBS LP03 HADT H. Amygdala Depression, pBS LP03 subtracted H6AS Hl-60, untreated, subtracted Uni-ZAP XR LP03 H6ES HL-60, PMA 4H, subtracted Uni-ZAP XR LP03 H6BS HL-60, RA 4h, Subtracted Uni-ZAP XR LP03 H6CS HL-60, PMA 1d, subtracted Uni-ZAP XR LP03 HTXJ HTXK Activated T- Uni-ZAP XR LP03 cell(12 h)/Thiouridine-re- excision HMSA HMSB HMSC HMSD Monocyte activated Uni-ZAP XR LP03 HMSE HMSF HMSG HMSH HMSI HMSJ HMSK HAGA HAGB HAGC HAGD Human Amygdala Uni-ZAP XR LP03 HAGE HAGF HSRA HSRB HSRE STROMAL - Uni-ZAP XR LP03 OSTEOCLASTOMA HSRD HSRF HSRG HSRH Human Osteoclastoma Stromal Uni-ZAP XR LP03 Cells - unamplified HSQA HSQB HSQC HSQD Stromal cell TF274 Uni-ZAP XR LP03 HSQE HSQF HSQG HSKA HSKB HSKC HSKD Smooth muscle, serum treated Uni-ZAP XR LP03 HSKE HSKF HSKZ HSLA HSLB HSLC HSLD Smooth muscle, control Uni-ZAP XR LP03 HSLE HSLF HSLG HSDA HSDD HSDE HSDF Spinal cord Uni-ZAP XR LP03 HSDG HSDH HPWS Prostate-BPH subtracted II pBS LP03 HSKW HSKX HSKY Smooth Muscle - HASTE pBS LP03 normalized HFPB HFPC HFPD H. Frontal cortex, epileptic; re- Uni-ZAP XR LP03 excision HSDI HSDJ HSDK Spinal Cord, re-excision Uni-ZAP XR LP03 HSKN HSKO Smooth Muscle Serum Treated, pBS LP03 Norm HSKG HSKH HSKI Smooth muscle, serum pBS LP03 induced, re-exc HFCA HFCB HFCC HFCD Human Fetal Brain Uni-ZAP XR LP04 HFCE HFCF HPTA HPTB HPTD Human Pituitary Uni-ZAP XR LP04 HTHB HTHC HTHD Human Thymus Uni-ZAP XR LP04 HE6B HE6C HE6D HE6E HE6F Human Whole Six Week Old Uni-ZAP XR LP04 HE6G HE6S Embryo HSSA HSSB HSSC HSSD Human Synovial Sarcoma Uni-ZAP XR LP04 HSSE HSSF HSSG HSSH HSSI HSSJ HSSK HE7T 7 Week Old Early Stage Human, Uni-ZAP XR LP04 subtracted HEPA HEPB HEPC Human Epididymus Uni-ZAP XR LP04 HSNA HSNB HSNC HSNM Human Synovium Uni-ZAP XR LP04 HSNN HPFB HPFC HPFD HPFE Human Prostate Cancer, Stage C Uni-ZAP XR LP04 fraction HE2A HE2D HE2E HE2H HB2I 12 Week Old Early Stage Uni-ZAP XR LP04 HE2M HE2N HE2O Human HB2B HE2C HE2F HE2G HE2P 12 Week Old Early Stage Uni-ZAP XR LP04 HE2Q Human, II HPTS HPTT HPTU Human Pituitary, subtracted Uni-ZAP XR LP04 HAUA HAUB HAUC Amniotic Cells - TNF induced Uni-ZAP XR LP04 HAQA HAQB HAQC HAQD Amniotic Cells - Primary Uni-ZAP XR LP04 Culture HWTA HWTB HWTC wilm's tumor Uni-ZAP XR LP04 HBSD Bone Cancer, re-excision Uni-ZAP XR LP04 HSGB Salivary gland, re-excision Uni-ZAP XR LP04 HSJA HSJB HSJC Smooth muscle-ILb induced Uni-ZAP XR LP04 HSXA HSKB HSXC HSXD Human Substantia Nigra Uni-ZAP XR LP04 HSHA HSHB HSHC Smooth muscle, IL1b induced Uni-ZAP XR LP04 HOUA HOUB HOUC HOUD Adipocytes Uni-ZAP XR LP04 HOUE HPWA HPWB HPWC HPWD Prostate BPH Uni-ZAP XR LP04 HPWE HELA HELB HELC HELD Endothelial cells-control Uni-ZAP XR LP04 HELE HELF HELG HELH HEMA HEMB HEMC HEMD Endothelial-induced Uni-ZAP XR LP04 HEME HEMF HEMG HEMH HBIA HBIB HBIC Human Brain, Striatum Uni-ZAP XR LP04 HHSA HHSB HHSC HHSD Human Uni-ZAP XR LP04 HHSE Hypothalmus, Schizophrenia HNGA HNGB HNGC HNGD neutrophils control Uni-ZAP XR LP04 HNGE HNGF HNGG HNGH HNGI HNGJ HNHA HNHB HNHC HNHD Neutrophils IL-1 and LPS Uni-ZAP XR LP04 HNHE HNHF HNHG HNHH induced HNHI HNHJ HSDB HSDC STRIATUM DEPRESSION Uni-ZAP XR LP04 HHPT Hypothalamus Uni-ZAP XR LP04 HSAT HSAU HSAV HSAW Anergic T-cell Uni-ZAP XR LP04 HSAX USAY HSAZ HBMS HBMT HBMU HBMV Bone marrow Uni-ZAP XR LP04 HBMW HBMX HOEA HOEB HOEC HOED Osteoblasts Uni-ZAP XR LP04 HOEE HOEF HOEJ HAIA HAIB HAIC HAID HAIE Epithelial-TNFa and INF Uni-ZAP XR LP04 HAIF induced HTGA HTGB HTGC HTGD Apoptotic T-cell Uni-ZAP XR LP04 HMCA HMCB HMCC HMCD Macrophage-oxLDL Uni-ZAP XR LP04 HMCE HMAA HMAB HMAC HMAD Macrophage (GM-CSF treated) Uni-ZAP XR LP04 HMAE HMAF HMAG HPHA Normal Prostate Uni-ZAP XR LP04 HPIA HPIB HPIC LNCAP prostate cell line Uni-ZAP XR LP04 HPJA HPJB HPJC PC3 Prostate cell line Uni-ZAP XR LP04 HOSE HOSF HOSG Human Osteoclastoma, re- Uni-ZAP XR LP04 excision HTGE HTGF Apoptotic T-cell, re-excision Uni-ZAP XR LP04 HMAJ HMAK H Macrophage (GM-CSF Uni-ZAP XR LP04 treated), re-excision HACB HACC HACD Human Adipose Tissue, re- Uni-ZAP XR LP04 excision HFPA H. Frontal Cortex, Epileptic Uni-ZAP XR LP04 HFAA HFAB HFAC HFAD Alzheimer's, spongy change Uni-ZAP XR LP04 HFAE HFAM Frontal Lobe, Dementia Uni-ZAP XR LP04 HMIA HMIB HMIC Human Manic Depression Uni-ZAP XR LP04 Tissue HTSA HTSE HTSF HTSG Human Thymus pBS LP05 HTSH HPBA HPBB HPBC HPBD Human Pineal Gland pBS LP05 HPBE HSAA HSAB HSAC HSA 172 Cells pBS LP05 HSBA HSBB HSBC HSBM HSC172 cells pBS LP05 HJAA HJAB HJAC HJAD Jurkat T-cell G1 phase pBS LP05 HJBA HJBB HJBC HJBD Jurkat T-Cell, S phase pBS LP05 HAFA HAFB Aorta endothelial cells + TNF-a pBS LP05 HAWA HAWB HAWC Human White Adipose pBS LP05 HTNA HTNB Human Thyroid pBS LP05 HONA Normal Ovary, Premenopausal pBS LP05 HARA HARB Human Adult Retina pBS LP05 HLJA HLJB Human Lung pCMVSport 1 LP06 HOFM HOFN HOFO H. Ovarian Tumor, II, OV5232 pCMVSport 2.0 LP07 HOGA HOGB HOGC OV 10-3-95 pCMVSport 2.0 LP07 HCGL CD34+cells, II pCMVSport 2.0 LP07 HDLA Hodgkin's Lymphoma I pCMVSport 2.0 LP07 HDTA HDTB HDTC HDTD Hodgkin's Lymphoma II pCMVSport 2.0 LP07 HDTE HKAA HKAB HKAC HKAD Keratinocyte pCMVSport 2.0 LP07 HKAE HKAF HKAG HKAH HCIM CAFFINDER, Crohn's Disease, pCMVSport 2.0 LP07 lib 2 HKAL Keratinocyte, lib 2 pCMVSport 2.0 LP07 HKAT Keratinocyte, lib 3 pCMVSport 2.0 LP07 HNDA Nasal polyps pCMVSport 2.0 LP07 HDRA H. Primary Dendritic Cells, lib 3 pCMVSport 2.0 LP07 HOHA HOHB HOHC Human Osteoblasts II pCMVSport 2.0 LP07 HLDA HLDB HLDC Liver, Hepatoma pCMVSport 3.0 LP08 HLDN HLDO HLDP Human Liver, normal pCMVSport 3.0 LP08 HMTA pBMC stimulated w/ poly I/C pCMVSport 3.0 LP08 HNTA NTERA2, control pCMVSport 3.0 LP08 HDPA HDPB HDPC HDPD Primary Dendritic Cells, lib 1 pCMVSport 3.0 LP08 HDPF HDPG HDPH HDPI HDPJ HDPK HDPM HDPN HDPO HDPP Primary Dendritic cells, frac 2 pCMVSport 3.0 LP08 HMUA HMUB HMUC Myoloid Progenitor Cell Line pCMVSport 3.0 LP08 HHEA HHEB HHEC HHED T Cell helper I pCMVSport 3.0 LP08 HHEM HHEN HHEO HHEP T cell helper II pCMVSport 3.0 LP08 HEQA HEQB HEQC Human endometrial stromal cells pCMVSport 3.0 LP08 HJMA HJMB Human endometrial stromal pCMVSport 3.0 LP08 cells-treated with progesterone HSWA HSWB HSWC Human endometrial stromal pCMVSport 3.0 LP08 cells-treated with estradiol HSYA HSYB HSYC Human Thymus Stromal Cells pCMVSport 3.0 LP08 HLWA HLWB HLWC Human Placenta pCMVSport 3.0 LP08 HRAA HRAB HRAC Rejected Kidney, lib 4 pCMVSport 3.0 LP08 HMTM PCR, pBMC I/C treated PCRII LP09 HMJA H. Meniingima, M6 pSport 1 LP10 HMKA HMKB HMKC HMKD H. Meningima, M1 pSport 1 LP10 HMKE HUSG HUSI Human umbilical vein pSport 1 LP10 endothelial cells, IL-4 induced HUSX HUSY Human Umbilical Vein pSport 1 LP10 Endothelial Cells, uninduced HOFA Ovarian Tumor I, OV5232 pSport 1 LP10 HCFA HCFB HCFC HCFD T-Cell PHA 16 hrs pSport 1 LP10 HCFL HCFM HCFN HCFO T-Cell PHA 24 hrs pSport 1 LP10 HADA HADC HADD HADE Human Adipose pSport 1 LP10 HADF HADG HOVA HOVB HOVC Human Ovary pSport 1 LP10 HTWB HTWC HTWD HTWE Resting T-Cell Library, II pSport 1 LP10 HTWF HMMA Spleen metastic melanoma pSport 1 LP10 HLYA HLYB HLYC HLYD Spleen, Chronic lymphocytic pSport 1 LP10 HLYE leukemia HCGA CD34+ cell, I pSport 1 LP10 HEOM HEON Human Eosinophils pSport 1 LP10 HTDA Human Tonsil, Lib 3 pSport 1 LP10 HSPA Salivary Gland, Lib 2 pSport 1 LP10 HCHA HCHB HCHC Breast Cancer cell line, MDA 36 pSport 1 LP10 HCHM HCHN Breast Cancer Cell line, pSport 1 LP10 angiogenic HCIA Crohn's Disease pSport 1 LP10 HDAA HDAB HDAC HEL cell line pSport 1 LP10 HABA Human Astrocyte pSport 1 LP10 HUFA HUFB HUFC Ulcerative Colitis pSport 1 LP10 HNTM NTERA2 + retinoic acid, 14 pSport 1 LP10 days HDQA Primary Dendritic pSport 1 LP10 cells, CapFinder2, frac 1 HDQM Primary Dendritic Cells, pSport 1 LP10 CapFinder, frac 2 HLDX Human Liver, normal, CapFinder pSport 1 LP10 HULA HULB HULC Human Dermal Endothelial pSport 1 LP10 Cells, untreated HUMA Human Dermal Endothelial pSport 1 LP10 cells, treated HCJA Human Stromal Endometrial pSport 1 LP10 fibroblasts, untreated HCJM Human Stromal endometrial pSport 1 LP10 fibroblasts, treated w/ estradiol HEDA Human Stromal endometrial pSport 1 LP10 fibroblasts, treated with progesterone HFNA Human ovary tumor cell pSport 1 LP10 OV350721 HKGA HKGB HKGC HKGD Merkel Cells pSport 1 LP10 HISA HISB HISC Pancreas Islet Cell Tumor pSport 1 LP10 HLSA Skin, burned pSport 1 LP10 HBZA Prostate, BPH, Lib 2 pSport 1 LP10 HBZS Prostate BPH, Lib 2, subtracted pSport 1 LP10 HFIA HFIB HFIC Synovial Fibroblasts (control) pSport 1 LP10 HFIH HFII HFIJ Synovial hypoxia pSport 1 LP10 HFIT HFIU HFIV Synovial IL-1/TNF stimulated pSport 1 LP10 HGCA Messangial cell, frac 1 pSport 1 LP10 HMVA HMVB HMVC Bone Marrow Stromal Cell, pSport 1 LP10 untreated HFIX HFIY HFIZ Synovial Fibroblasts (Il1/TNF), pSport 1 LP10 subt HFOX HFOY HFOZ Synovial hypoxia-RSF pSport 1 LP10 subtracted HMQA HMQB HMQC HMQD Human Activated Monocytes Uni-ZAP XR LP11 HLIA HLIB HLIC Human Liver pCMVSport 1 LP012 HHBA HHBB HHBC HHBD Human Heart pCMVSport 1 LP012 HHBE HBBA HBBB Human Brain pCMVSport 1 LP012 HLJA HLJB HLJC HLJD HLJE Human Lung pCMVSport 1 LP012 HOGA HOGB HOGC Ovarian Tumor pCMVSport 2.0 LP012 HTJM Human Tonsils, Lib 2 pCMVSport 2.0 LP012 HAMF HAMG KMH2 pCMVSport 3.0 LP012 HAJA HAJB HAJC L428 pCMVSport 3.0 LP012 HWBA HWBB HWBC HWBD Dendritic cells, pooled pCMVSport 3.0 LP012 HWBE HWAA HWAB HWAC HWAD Human Bone Marrow, treated pCMVSport 3.0 LP012 HWAE HYAA HYAB HYAC B Cell lymphoma pCMVSport 3.0 LP012 HWHG HWHH HWHI Healing groin wound, 6.5 hours pCMVSport 3.0 LP012 post incision HWHP HWHQ HWHR Healing groin wound; 7.5 hours pCMVSport 3.0 LP012 post incision HARM Healing groin wound - zero hr pCMVSport 3.0 LP012 post-incision (control) HBIM Olfactory epithelium; pCMVSport 3.0 LP012 nasalcavity HWDA Healing Abdomen wound; pCMVSport 3.0 LP012 70&90 min post incision HWEA Healing Abdomen Wound; 15 pCMVSport 3.0 LP012 days post incision HWJA Healing Abdomen pCMVSport 3.0 LP012 Wound; 21&29 days HNAL Human Tongue, frac 2 pSport 1 LP012 HMJA H. Meniingima, M6 pSport 1 LP012 HMKA HMKB HMKC HMKD H. Meningima, M1 pSport 1 LP012 HMKE HOFA Ovarian Tumor I, OV5232 pSport 1 LP012 HCFA HCFB HCFC HCFD T-Cell PHA 16 hrs pSport 1 LP012 HCFL HCFM HCFN HCFO T-Cell PHA 24 hrs pSport 1 LP012 HMMA HMMB HMMC Spleen metastic melanoma pSport 1 LP012 HTDA Human Tonsil, Lib 3 pSport 1 LP0L2 HDBA Human Fetal Thymus pSport 1 LP012 HDUA Pericardium pSport 1 LP012 HBZA Prostate, BPH, Lib 2 pSport 1 LP012 HWCA Larynx tumor pSport 1 LP012 HWKA Normal lung pSport 1 LP012 HSMB Bone marrow stroma, treated pSport 1 LP012 HBHM Normal trachea pSport 1 LP012 HLFC Human Larynx pSport 1 LP012 HLRB Siebben Polyposis pSport 1 LP012 HNIA Mammary Gland pSport 1 LP012 HNJB Palate carcinoma pSport 1 LP012 HNKA Palate normal pSport 1 LP012 HMZA Pharynx carcinoma pSport 1 LP012 HABG Cheek Carcinoma pSport 1 LP012 HMZM Pharynx Carcinoma pSport 1 LP012 HDRM Larynx Carcinoma pSport 1 LP012 HVAA Pancreas normal PCA4 No pSport 1 LP012 HICA Tongue carcinoma pSport 1 LP012 HUKA HUKB HUKC HUKD Human Uterine Cancer Lambda ZAP II LP013 HUKE HFFA Human Fetal Brain, random Lambda ZAP II LP013 primed HTUA Activated T-cell labeled with 4- Lambda ZAP II LP013 thioluri HBQA Early Stage Human Brain, Lambda ZAP II LP013 random primed HMEB Human microvascular Lambda ZAP II LP013 Endothelial cells, fract. B HUSH Human Umbilical Vein Lambda ZAP II LP013 Endothelial cells, fract. A, re- excision HLQC HLQD Hepatocellular tumor, re- Lambda ZAP II LP013 excision HTWJ HTWK HTWL Resting T-cell, re-excision Lambda ZAP II LP013 HF6S Human Whole 6 week Old pBluescript LP013 Embryo (II), subt HHPS Human Hippocampus, pBluescript LP013 subtracted HL1S LNCAP, differential expression pBluescript LP013 HLHS HLHT Early Stage Human Lung, pBluescript LP013 Subtracted HSUS Supt cells, cyclohexamide pBluescript LP013 treated, subtracted HSUT Supt cells, cyclohexamide pBluescript LP013 treated, differentially expressed HSDS H. Striatum Depression, pBluescript LP013 subtracted HPTZ Human Pituitary, Subtracted VII pBluescript LP013 HSDX H. Striatum Depression, subt II pBluescript LP013 HSDZ H. Striatum Depression, subt pBluescript LP013 HPBA HPBB HPBC HPBD Human Pineal Gland pBluescript SK− LP013 HPBE HRTA Colorectal Tumor pBluescript SK− LP013 HSBA HSBB HSBC HSBM HSC172 cells pBluescript SK− LP013 HJAA HJAB HJAC HJAD Jurkat T-cell G1 phase pBluescript SK− LP013 HJBA HJBB HJBC HJBD Jurkat T-cell, S1 phase pBluescript SK− LP013 HTNA HTNB Human Thyroid pBluescript SK− LP013 HAHA HAHB Human Adult Heart Uni-ZAP XR LP013 HE6A Whole 6 week Old Embryo Uni-ZAP XR LP013 HFCA HFCB HFCC HFCD Human Fetal Brain Uni-ZAP XR LP013 HFCE HFKC HFKD HFKE HFKF Human Fetal Kidney Uni-ZAP XR LP013 HFKG HGBA HGBD HGBE HGBF Human Gall Bladder Uni-ZAP XR LP013 HGBG HPRA HPRB HPRC HPRD Human Prostate Uni-ZAP XR LP013 HTEA HTEB HTEC HTED Human Testes Uni-ZAP XR LP013 HTEE HTTA HTTB HTTC HTTD Human Testes Tumor Uni-ZAP XR LP013 HTTE HYBA HYBB Human Fetal Bone Uni-ZAP XR LP013 HFLA Human Fetal Liver Uni-ZAP XR LP013 HHFB HHFC HHFD HHFE Human Fetal Heart Uni-ZAP XR LP013 HHFF HUVB HUVC HUVD HUVE Human Umbilical Vein, End. Uni-ZAP XR LP013 remake HTHB HTHC HTHD Human Thymus Uni-ZAP XR LP013 HSTA HSTB HSTC HSTD Human Skin Tumor Uni-ZAP XR LP013 HTAA HTAB HTAC HTAD Human Activated T-cells Uni-ZAP XR LP013 HTAE HFEA HFEB HFEC Human Fetal Epithelium (skin) Uni-ZAP XR LP013 HJPA HJPB HJPC HJPD Human Jurkat Membrane Bound Uni-ZAP XR LP013 Polysomes HESA Human Epithelioid Sarcoma Uni-ZAP XR LP013 HALS Human Adult Liver, Subtracted Uni-ZAP XR LP013 HFTA HFTB HFTC HFTD Human Fetal Dura Mater Uni-ZAP XR LP013 HCAA HCAB HCAC Cem cells, cyclohexamide Uni-ZAP XR LP013 treated HRGA HRGB HRGC HRGD Raji Cells, cyclohexamide Uni-ZAP XR LP013 treated HE9A HE9B HE9C HE9D Nine Week Old Early Stage Uni-ZAP XR LP013 HE9E Human HSFA Human Fibrosarcoma Uni-ZAP XR LP013 HATA HATB HATC HATD Human Adrenal Gland Tumor Uni-ZAP XR LP013 HATE HTRA Human Trachea Tumor Uni-ZAP XR LP013 HE2A HE2D HE2E HE2H HE2I 12 Week Old Early Stage Uni-ZAP XR LP013 Human HE2B HE2C HE2F HE2G HE2P 12 Week Old Early Stage Uni-ZAP XR LP013 Human, II HNEA HNEB HNEC HNED Human Neutrophil Uni-ZAP XR LP013 HNEE HBGA Human Primary Breast Cancer Uni-ZAP XR LP013 HPTS HPTT HPTU Human Pituitary, subtracted Uni-ZAP XR LP013 HMQA HMQB HMQC HMQD Human Activated Monocytes Uni-ZAP XR LP013 HOAA HOAB HOAC Human Osteosarcoma Uni-ZAP XR LP013 HTOA HTOD HTOE HTOF human tonsils Uni-ZAP XR LP013 HTOG HMGB Human OB MG63 control Uni-ZAP XR LP013 fraction I HOPB Human OB HOS control fraction I Uni-ZAP XR LP013 HOQB Human OB HOS treated (1 nM Uni-ZAP XR LP013 E2) fraction I HAUA HAUB HAUC Amniotic Cells - TNF induced Uni-ZAP XR LP013 HAQA HAQB HAQC HAQD Amniotic Cells - Primary Uni-ZAP XR LP013 Culture HROA HROC HUMAN STOMACH Uni-ZAP XR LP013 HBJA HBJB HBJC HBJD HBJE HUMAN B CELL Uni-ZAP XR LP013 LYMPHOMA HODA HODB HODC HODD human ovarian cancer Uni-ZAP XR LP013 HCPA Corpus Callosum Uni-ZAP XR LP013 HSOA stomach cancer (human) Uni-ZAP XR LP013 HERA SKIN Uni-ZAP XR LP013 HMDA Brain-medulloblastoma Uni-ZAP XR LP013 HGLA HGLB HGLD Glioblastoma Uni-ZAP XR LP013 HWTA HWTB HWTC wilm's tumor Uni-ZAP XR LP013 HEAA H. Atrophic Endometrium Uni-ZAP XR LP013 HAPN HAPO HAPP HAPQ Human Adult Pulmonary; re- Uni-ZAP XR LP013 HAPR excision HLTG HLTH Human T-cell lymphoma; re- Uni-ZAP XR LP013 excision HAHC HAHD HAHE Human Adult Heart; re-excision Uni-ZAP XR LP013 HAGA HAGB HAGC HAGD Human Amygdala Uni-ZAP XR LP013 HAGE HSJA HSJB HSJC Smooth muscle-ILb induced Uni-ZAP XR LP013 HSHA HSHB HSHC Smooth muscle, IL1b induced Uni-ZAP XR LP013 HPWA HPWB HPWC HPWD Prostate BPH Uni-ZAP XR LP013 HPWE HPIA HPIB HPIC LNCAP prostate cell line Uni-ZAP XR LP013 HPJA HPJB HPJC PC3 Prostate cell line Uni-ZAP XR LP013 HBTA Bone Marrow Stroma, Uni-ZAP XR LP013 TNF&LPS ind HMCF HMCG HMCH HMCI Macrophage-oxLDL; re-excision Uni-ZAP XR LP013 HMCJ HAGG HAGH HAGI Human Amygdala; re-excision Uni-ZAP XR LP013 HACA H. Adipose Tissue Uni-ZAP XR LP013 HKFB K562 + PMA (36 hrs), re- ZAP Express LP013 excision HCWT HCWU HCWV CD34 positive cells (cord ZAP Express LP013 blood), re-ex HBWA Whole brain ZAP Express LP013 HBXA HBXB HBXC HBXD Human Whole Brain #2 - Oligo ZAP Express LP013 dT >1.5 Kb HAVM Temporal cortex-Alzheizmer pT-Adv LP014 HAVT Hippocampus, Alzheimer pT-Adv LP014 Subtracted HHAS CHME Cell Line Uni-ZAP XR LP014 HAJR Larynx normal pSport 1 LP014 HWLE HWLF HWLG HWLH Colon Normal pSport 1 LP014 HCRM HCRN HCRO Colon Carcinoma pSport 1 LP014 HWLI HWLJ HWLK Colon Normal pSport 1 LP014 HWLQ HWLR HWLS HWLT Colon Tumor pSport 1 LP014 HBFM Gastrocnemius Muscle pSport 1 LP014 HBOD HBOE Quadriceps Muscle pSport 1 LP014 HBKD HBKE Soleus Muscle pSport 1 LP014 HCCM Pancreatic Langerhans pSport 1 LP014 HWGA Larynx carcinoma pSport 1 LP014 HWGM HWGN Larynx carcinoma pSport 1 LP014 HWLA HWLB HWLC Normal colon pSport 1 LP014 HWLM HWLN Colon Tumor pSport 1 LP014 HVAM HVAN HVAO Pancreas Tumor pSport 1 LP014 HWGQ Larynx carcinoma pSport 1 LP014 HAQM HAQN Salivary Gland pSport 1 LP014 HASM Stomach; normal pSport 1 LP014 HBCM Uterus; normal pSport 1 LP014 HCDM Testis; normal pSport 1 LP014 HDJM Brain; normal pSport 1 LP014 HEFM Adrenal Gland, normal pSport 1 LP014 HBAA Rectum normal pSport 1 LP014 HFDM Rectum tumour pSport 1 LP014 HGAM Colon, normal pSport 1 LP014 HHMM Colon, tumour pSport 1 LP014 HCLB HCLC Human Lung Cancer Lambda Zap II LP015 HRLA L1 Cell line ZAP Express LP015 HHAM Hypothalamus, Alzheimer's pCMVSport 3.0 LP015 HKBA Ku 812F Basophils Line pSport 1 LP015 HS2S Saos2, Dexamethosome Treated pSport 1 LP016 HA5A Lung Carcinoma A549 pSport 1 LP016 TNFalpha activated HTFM TF-1 Cell Line GM-CSF Treated pSport 1 LP016 HYAS Thyroid Tumour pSport 1 LP016 HUTS Larynx Normal pSport 1 LP016 HXOA Larynx Tumor pSport 1 LP016 HEAH Ea.hy.926 cell line pSport 1 LP016 HINA Adenocarcinoma Human pSport 1 LP016 HRMA Lung Mesothelium pSport 1 LP016 HLCL Human Pre-Differentiated Uni-Zap XR LP017 Adipocytes HS2A Saos2 Cells pSport 1 LP020 HS2I Saos2 Cells; Vitamin D3 Treated pSport 1 LP020 HUCM CHME Cell Line, untreated pSport 1 LP020 HEPN Aryepiglottis Normal pSport 1 LP020 HPSN Sinus Piniformis Tumour pSport 1 LP020 HNSA Stomach Normal pSport 1 LP020 HNSM Stomach Tumour pSport 1 LP020 HNLA Liver Normal Met5No pSport 1 LP020 HUTA Liver Tumour Met 5 Tu pSport 1 LP020 HOCN Colon Normal pSport 1 LP020 HOCT Colon Tumor pSport 1 LP020 HTNT Tongue Tumour pSport 1 LP020 HLXN Larynx Normal pSport 1 LP020 HLXT Larynx Tumour pSport 1 LP020 HTYN Thymus pSport 1 LP020 HPLN Placenta pSport 1 LP020 HTNG Tongue Normal pSport 1 LP020 HZAA Thyroid Normal (SDCA2 No) pSport 1 LP020 HWES Thyroid Thyroiditis pSport 1 LP020 HFHD Ficolled Human Stromal Cells, pTrip1Ex2 LP021 5Fu treated HFHM, HFHN Ficolled Human Stromal Cells, pTrip1Ex2 LP021 Untreated HPCI Hep G2 Cells, lambda library lambda Zap-CMV LP021 XR HBCA, HBCB, HBCC H. Lymph node breast Cancer Uni-ZAP XR LP021 HCOK Chondrocytes pSPORT 1 LP022 HDCA, HDCB, HDCC Dendritic Cells From CD34 pSPORT 1 LP022 Cells HDMA, HDMB CD40 activated monocyte pSPORT 1 LP022 dendritic cells HDDM, HDDN, HDDO LPS activated derived dendritic pSPORT 1 LP022 cells HPCR Hep G2 Cells, PCR library lambda Zap-CMV LP022 XR HAAA, HAAB, HAAC Lung, Cancer (4005313A3): pSPORT 1 LP022 Invasive Poorly Differentiated Lung Adenocarcinoma HIPA, HIPB, HIPC Lung, Cancer (4005163 B7): pSPORT 1 LP022 Invasive, Poorly Diff. Adenocarcinoma, Metastatic HOOH, HOOI Ovary, Cancer: (4004562 B6) pSPORT 1 LP022 Papillary Serous Cystic Neoplasm, Low Malignant Pot HIDA Lung, Normal: (4005313 B1) pSPORT 1 LP022 HUJA, HUJB, HUJC, HUJD, HUJE B-Cells pCMVSport 3.0 LP022 HNOA, HNOB, HNOC, HNOD Ovary, Normal: (9805C040R) pSPORT 1 LP022 HNLM Lung, Normal: (4005313 B1) pSPORT 1 LP022 HSCL Stromal Cells pSPORT 1 LP022 HAAX Lung, Cancer: (4005313 A3) pSPORT 1 LP022 Invasive Poorly-differentiated Metastatic lung adenocarcinoma HUUA, HUUB, HUUC, HUUD B-cells (unstimulated) pTrip1Ex2 LP022 HWWA, HWWB, HWWC, HWWD B-cells (stimulated) pSPORT 1 LP022 HWWE, HWWF, HWWG HCCC Colon, Cancer: (9808C064R) CMVSport 3.0 LP023 HPDO HPDP HPDQ HPDR Ovary, Cancer (9809C332): pSport 1 LP023 HPD Poorly differentiated adenocarcinoma HPCO HPCP HPCQ HPCT Ovary, Cancer (15395A1F): pSport 1 LP023 Grade II Papillary Carcinoma HOCM HOCO HOCP HOCQ Ovary, Cancer: (15799A1F) pSport 1 LP023 Poorly differentiated carcinoma HCBM HCBN HCBO Breast, Cancer (4004943 A5) pSport 1 LP023 HNBT HNBU HNBV Breast, Normal: (4005522B2) pSport 1 LP023 HBCP HBCQ Breast, Cancer: (4005522 A2) pSport 1 LP023 HBCJ Breast, Cancer: (9806C012R) pSport 1 LP023 HSAM HSAN Stromal cells 3.88 pSport 1 LP023 HVCA HVCB HVCC HVCD Ovary, Cancer: (4004332 A2) pSport 1 LP023 HSCK HSEN HSEO Stromal cells (HBM3.18) pSport 1 LP023 HSCP HSCQ stromal cell clone 2.5 pSport 1 LP023 HUXA Breast Cancer: (4005385 A2) pSport 1 LP023 HCOM HCON HCOO HCOP Ovary, Cancer (4004650 A3): pSport 1 LP023 HCOQ Well-Differentiated Micropapillary Serous Carcinoma HBNM Breast, Cancer: (9802C020E) pSport 1 LP023 HVVA HVVB HVVC HVVD Human Bone Marrow, treated pSport 1 LP023 HVVE

Two nonlimiting examples are provided below for isolating a particular clone from the deposited sample of plasmid cDNAs cited for that clone in Table 7. First, a plasmid is directly isolated by screening the clones using a polynucleotide probe corresponding to the nucleotide sequence of SEQ ID NO:X.

Particularly, a specific polynucleotide with 30-40 nucleotides is synthesized using an Applied Biosystems DNA synthesizer according to the sequence reported. The oligonucleotide is labeled, for instance, with ³²P-γ-ATP using T4 polynucleotide kinase and purified according to routine methods. (E.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring, N.Y. (1982)). The plasmid mixture is transformed into a suitable host, as indicated above (such as XL-1 Blue (Stratagene)) using techniques known to those of skill in the art, such as those provided by the vector supplier or in related publications or patents cited above. The transformants are plated on 1.5% agar plates (containing the appropriate selection agent, e.g., ampicillin) to a density of about 150 transformants (colonies) per plate. These plates are screened using Nylon membranes according to routine methods for bacterial colony screening (e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Edit., (1989), Cold Spring Harbor Laboratory Press, pages 1.93 to 1.104), or other techniques known to those of skill in the art.

Alternatively, two primers of 17-20 nucleotides derived from both ends of the nucleotide sequence of SEQ ID NO:X are synthesized and used to amplify the desired cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 25 μl of reaction mixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-5 mM MgCl₂, 0.01% (w/v) gelatin, 20 μM each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturation at 94° C. for 1 min; annealing at 55° C. for 1 min; elongation at 72° C. for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis and the DNA band with expected molecular weight is excised and purified. The PCR product is verified to be the selected sequence by subcloning and sequencing the DNA product.

Several methods are available for the identification of the 5′ or 3′ non-coding portions of a gene which may not be present in the deposited clone. These methods include but are not limited to, filter probing, clone enrichment using specific probes, and protocols similar or identical to 5′ and 3′ “RACE” protocols which are well known in the art For instance, a method similar to 5′ RACE is available for generating the missing 5′ end of a desired full-length transcript (Fromont-Racine et al., Nucleic Acids Res. 21(7):1683-1684 (1993)).

Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of a population of RNA presumably containing full-length gene RNA transcripts. A primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest is used to PCR amplify the 5′ portion of the desired full-length gene. This amplified product may then be sequenced and used to generate the full length gene.

This above method starts with total RNA isolated from the desired source, although poly-A+ RNA can be used. The RNA preparation can then be treated with phosphatase if necessary to eliminate 5′ phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase should then be inactivated and the RNA treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5′ ends of messenger RNAs. This reaction leaves a 5′ phosphate group at the 5′ end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase.

This modified RNA preparation is used as a template for first strand cDNA synthesis using a gene specific oligonucleotide. The first strand synthesis reaction is used as a template for PCR amplification of the desired 5′ end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the]nown sequence of the gene of interest. The resultant product is then sequenced and analyzed to confirm that the 5′ end sequence belongs to the desired gene.

Example 2 Isolation of Genomic Clones Corresponding to a Polynucleotide

A human genomic P1 library (Genomic Systems, Inc.) is screened by PCR using primers selected for the sequence corresponding to SEQ ID NO:X according to the method described in Example 1. (See also, Sambrook.)

Example 3 Tissue Specific Expression Analysis

The Human Genome Sciences, Inc. (HGS) database is derived from sequencing tissue and/or disease specific cDNA libraries. Libraries generated from a particular tissue are selected and the specific tissue expression pattern of EST groups or assembled contigs within these libraries is determined by comparison of the expression patterns of those groups or contigs within the entire database. ESTs and assembled contigs which show tissue specific expression are selected.

The original clone from which the specific EST sequence was generated, or in the case of an assembled contig, the clone from which the 5′ most EST sequence was generated, is obtained from the catalogued library of clones and the insert amplified by PCR using methods known in the art. The PCR product is denatured and then transferred in 96 or 384 well format to a nylon membrane (Schleicher and Scheull) generating an array filter of tissue specific clones. Housekeeping genes, maize genes, and known tissue specific genes are included on the filters. These targets can be used in signal normalization and to validate assay sensitivity. Additional targets are included to monitor probe length and specificity of hybridization.

Radioactively labeled hybridization probes are generated by first strand cDNA synthesis per the manufacturer's instructions (Life Technologies) from mRNA/RNA samples prepared from the specific tissue being analyzed (e.g., prostate, prostate cancer, ovarian, ovarian cancer, etc.). The hybridization probes are purified by gel exclusion chromatography, quantitated, and hybridized with the array filters in hybridization bottles at 65° C. overnight. The filters are washed under stringent conditions and signals are captured using a Fuji phosphorimager.

Data is extracted using AIS software and following background subtraction, signal normalization is performed. This includes a normalization of filter-wide expression levels between different experimental runs. Genes that are differentially expressed in the tissue of interest are identified.

Example 4 Chromosomal Mapping of the Polynucleotides

An oligonucleotide primer set is designed according to the sequence at the 5′ end of SEQ ID NO:X. This primer preferably spans about 100 nucleotides. This primer set is then used in a polymerase chain reaction under the following set of conditions: 30 seconds, 95° C.; 1 minute, 56° C.; 1 minute, 70° C. This cycle is repeated 32 times followed by one 5 minute cycle at 70° C. Human, mouse, and hamster DNA is used as template in addition to a somatic cell hybrid panel containing individual chromosomes or chromosome fragments (Bios, Inc). The reactions are analyzed on either 8% polyacrylamide gels or 3.5% agarose gels. Chromosome mapping is determined by the presence of an approximately 100 bp PCR fragment in the particular somatic cell hybrid.

Example 5 Bacterial Expression of a Polypeptide

A polynucleotide encoding a polypeptide of the present invention is amplified using PCR oligonucleotide primers corresponding to the 5′ and 3′ ends of the DNA sequence, as outlined in Example 1, to synthesize insertion fragments. The primers used to amplify the cDNA insert should preferably contain restriction sites, such as BamHI and XbaI, at the 5′ end of the primers in order to clone the amplified product into the expression vector. For example, BamHI and XbaI correspond to the restriction enzyme sites on the bacterial expression vector pQE-9. (Qiagen, Inc., Chatsworth, Calif.). This plasmid vector encodes antibiotic resistance (Amp^(r)), a bacterial origin of replication (ori), an IPTG-regulatable promoter/operator (P/0), a ribosome binding site (RBS), a 6-histidine tag (6-His), and restriction enzyme cloning sites.

The pQE-9 vector is digested with BamHI and XbaI and the amplified fragment is ligated into the pQE-9 vector maintaining the reading frame initiated at the bacterial RBS. The ligation mixture is then used to transform the E. coli strain M15/rep4 (Qiagen, Inc.) which contains multiple copies of the plasmid pREP4, which expresses the lacI repressor and also confers kanamycin resistance (Kan^(r)). Transformants are identified by their ability to grow on LB plates and ampicillin/kanamycin resistant colonies are selected. Plasmid DNA is isolated and confirmed by restriction analysis.

Clones containing the desired constructs are grown overnight (O/N) in liquid culture in LB media supplemented with both Amp (100 ug/ml) and Kan (25 ug/ml). The O/N culture is used to inoculate a large culture at a ratio of 1:100 to 1:250. The cells are grown to an optical density 600 (O.D.⁶⁰⁰) of between 0.4 and 0.6. IPTG (Isopropyl-B-D-thiogalacto pyranoside) is then added to a final concentration of 1 mM. IPTG induces by inactivating the lacI repressor, clearing the P/O leading to increased gene expression.

Cells are grown for an extra 3 to 4 hours. Cells are then harvested by centrifugation (20 mins at 6000×g). The cell pellet is solubilized in the chaotropic agent 6 Molar Guanidine HCl by stirring for 3-4 hours at 4° C. The cell debris is removed by centrifugation, and the supernatant containing the polypeptide is loaded onto a nickel-nitrilo-tri-acetic acid (“Ni-NTA”) affinity resin column (available from QIAGEN, Inc., supra). Proteins with a 6×His tag bind to the Ni-NTA resin with high affinity and can be purified in a simple one-step procedure (for details see: The QIAexpressionist (1995) QIAGEN, Inc., supra).

Briefly, the supernatant is loaded onto the column in 6 M guanidine-HCl, pH 8. The column is first washed with 10 volumes of 6 M guanidine-HCl, pH 8, then washed with 10 volumes of 6 M guanidine-HCl pH 6, and finally the polypeptide is eluted with 6 M guanidine-HCl, pH 5.

The purified protein is then renatured by dialyzing it against phosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus 200 mM NaCl. Alternatively, the protein can be successfully refolded while immobilized on the Ni-NTA column. The recommended conditions are as follows: renature using a linear 6M-1M urea gradient in 500 mM NaCl, 20% glycerol, 20 mM Tris/HCl pH 7.4, containing protease inhibitors. The renaturation should be performed over a period of 1.5 hours or more. After renaturation the proteins are eluted by the addition of 250 mM immidazole. Immidazole is removed by a final dialyzing step against PBS or 50 mM sodium acetate pH 6 buffer plus 200 mM NaCl. The purified protein is stored at 4° C. or frozen at −80° C.

In addition to the above expression vector, the present invention further includes an expression vector, called pHB4a (ATCC Accession Number 209645, deposited on Feb. 25, 1998) which contains phage operator and promoter elements operatively linked to a polynucleotide of the present invention, called pHE4a. (ATCC Accession Number 209645, deposited on Feb. 25, 1998.) This vector contains: 1) a neomycinphosphotransferase gene as a selection marker, 2) an E. coli origin of replication, 3) a T5 phage promoter sequence, 4) two lac operator sequences, 5) a Shine-Delgarno sequence, and 6) the lactose operon repressor gene (lacIq). The origin of replication (oriC) is derived from pUC19 (LTI, Gaithersburg, Md.). The promoter and operator sequences are made synthetically.

DNA can be inserted into the pHE4a by restricting the vector with NdeI and XbAI, BamHI, XhoI, or Asp718, running the restricted product on a gel, and isolating the larger fragment (the stuffer fragment should be about 310 base pairs). The DNA insert is generated according to the PCR protocol described in Example 1, using PCR primers having restriction sites for NdeI (5′ primer) and XbaI, BamHI, XhoI, or Asp718 (3′ primer). The PCR insert is gel purified and restricted with compatible enzymes. The insert and vector are ligated according to standard protocols.

The engineered vector could easily be substituted in the above protocol to express protein in a bacterial system.

Example 6 Purification of a Polypeptide from an Inclusion Body

The following alternative method can be used to purify a polypeptide expressed in E coli when it is present in the form of inclusion bodies. Unless otherwise specified, all of the following steps are conducted at 4-10° C.

Upon completion of the production phase of the E. coli fermentation, the cell culture is cooled to 4-10° C. and the cells harvested by continuous centrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of the expected yield of protein per unit weight of cell paste and the amount of purified protein required, an appropriate amount of cell paste, by weight, is suspended in a buffer solution containing 100 mM Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to a homogeneous suspension using a high shear mixer.

The cells are then lysed by passing the solution through a microfluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at 4000-6000 psi. The homogenate is then mixed with NaCl solution to a final concentration of 0.5 M NaCl, followed by centrifugation at 7000×g for 15 min. The resultant pellet is washed again using 0.5M NaCl, 100 mM Tris, 50 mM EDTA, pH 7.4.

The resulting washed inclusion bodies are solubilized with 1.5 M guanidine hydrochloride (GuHCl) for 2-4 hours. After 7000×g centrifugation for 15 min., the pellet is discarded and the polypeptide containing supernatant is incubated at 4° C. overnight to allow further GuHCl extraction.

Following high speed centrifugation (30,000×g) to remove insoluble particles, the GuHCl solubilized protein is refolded by quickly mixing the GuHCl extract with 20 volumes of buffer containing 50 mM sodium pH 4.5, 150 mM NaCl, 2 mM EDTA by vigorous stirring. The refolded diluted protein solution is kept at 4° C. without mixing for 12 hours prior to further purification steps.

To clarify the refolded polypeptide solution, a previously prepared tangential filtration unit equipped with 0.16 μm membrane filter with appropriate surface area (e.g., Filtron), equilibrated with 40 mM sodium acetate, pH 6.0 is employed. The filtered sample is loaded onto a cation exchange resin (e.g., Poros HS-50, Perseptive Biosystems). The column is washed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaCl in the same buffer, in a stepwise manner. The absorbance at 280 nm of the effluent is continuously monitored. Fractions are collected and further analyzed by SDS-PAGE.

Fractions containing the polypeptide are then pooled and mixed with 4 volumes of water. The diluted sample is then loaded onto a previously prepared set of tandem columns of strong anion (Poros HQ-50, Perseptive Biosystems) and weak anion (Poros CM-20, Perseptive Biosystems) exchange resins. The columns are equilibrated with 40 mM sodium acetate, pH 6.0. Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaCl. The CM-20 column is then eluted using a 10 column volume linear gradient ranging from 0.2 M NaCl, 50 mM sodium acetate, pH 6.0 to 1.0 M NaCl, 50 mM sodium acetate, pH 6.5. Fractions are collected under constant A₂₈₀ monitoring of the effluent. Fractions containing the polypeptide (determined, for instance, by 16% SDS-PAGE) are then pooled.

The resultant polypeptide should exhibit greater than 95% purity after the above refolding and purification steps. No major contaminant bands should be observed from Commassie blue stained 16% SDS-PAGE gel when 5 μg of purified protein is loaded. The purified protein can also be tested for endotoxin/LPS contamination, and typically the LPS content is less than 0.1 ng/ml according to LAL assays.

Example 7 Cloning and Expression of a Polypeptide in a Baculovirus Expression System

In this example, the plasmid shuttle vector pA2 is used to insert a polynucleotide into a baculovirus to express a polypeptide. This expression vector contains the strong polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus (AcMNPV) followed by convenient restriction sites such as BamHI, Xba I and Asp718. The polyadenylation site of the simian virus 40 (“SV40”) is used for efficient polyadenylation. For easy selection of recombinant virus, the plasmid contains the beta-galactosidase gene from E. coli under control of a weak Drosophila promoter in the same orientation, followed by the polyadenylation signal of the polyhedrin gene. The inserted genes are flanked on both sides by viral sequences for cell-mediated homologous recombination with wild-type viral DNA to generate a viable virus that express the cloned polynucleotide.

Many other baculovirus vectors can be used in place of the vector above, such as pAc373, pVL941, and pAcIM1, as one skilled in the art would readily appreciate, as long as the construct provides appropriately located signals for transcription, translation, secretion and the like, including a signal peptide and an in-frame AUG as required. Such vectors are described, for instance, in Luckow et al., Virology 170:31-39 (1989).

Specifically, the cDNA sequence contained in the deposited clone, including the AUG initiation codon, is amplified using the PCR protocol described in Example 1. If a naturally occurring signal sequence is used to produce the polypeptide of the present invention, the pA2 vector does not need a second signal peptide. Alternatively, the vector can be modified (pA2 GP) to include a baculovirus leader sequence, using the standard methods described in Summers et al., “A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures,” Texas Agricultural Experimental Station Bulletin No. 1555 (1987).

The amplified fragment is isolated from a 1% agarose gel using a commercially available kit (“Geneclean,” BIO 101 Inc., La Jolla, Calif.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1% agarose gel.

The plasmid is digested with the corresponding restriction enzymes and optionally, can be dephosphorylated using calf intestinal phosphatase, using routine procedures known in the art. The DNA is then isolated from a 1% agarose gel using a commercially available kit (“Geneclean” BIO 101 Inc., La Jolla, Calif.).

The fragment and the dephosphorylated plasmid are ligated together with T4 DNA ligase. E. coli HB101 or other suitable E. coli hosts such as XL-1 Blue (Stratagene Cloning Systems, La Jolla, Calif.) cells are transformed with the ligation mixture and spread on culture plates. Bacteria containing the plasmid are identified by digesting DNA from individual colonies and analyzing the digestion product by gel electrophoresis. The sequence of the cloned fragment is confirmed by DNA sequencing.

Five μg of a plasmid containing the polynucleotide is co-transfected with 1.0 μg of a commercially available linearized baculovirus DNA (“BaculoGold™ baculovirus DNA, Pharmingen, San Diego, Calif.), using the lipofection method described by Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417 (1987). One μg of BaculoGold™ virus DNA and 5 μg of the plasmid are mixed in a sterile well of a microtiter plate containing 50 μl of serum-free Grace's medium (Life Technologies Inc., Gaithersburg, Md.). Afterwards, 10 μl Lipofectin plus 90 μl Grace's medium are added, mixed and incubated for 15 minutes at room temperature. Then the transfection mixture is added drop-wise to Sf9 insect cells (ATCC CRL 1711) seeded in a 35 mm tissue culture plate with 1 ml Grace's medium without serum. The plate is then incubated for 5 hours at 27° C. The transfection solution is then removed from the plate and 1 ml of Grace's insect medium supplemented with 10% fetal calf serum is added. Cultivation is then continued at 27° C. for four days.

After four days the supernatant is collected and a plaque assay is performed, as described by Summers and Smith, spra. An agarose gel with “Blue Gal” (Life Technologies Inc., Gaithersburg) is used to allow easy identification and isolation of gal-expressing clones, which produce blue-stained plaques. (A detailed description of a “plaque assay” of this type can also be found in the user's guide for insect cell culture and baculovirology distributed by Life Technologies Inc., Gaithersburg, page 9-10.) After appropriate incubation, blue stained plaques are picked with the tip of a micropipettor (e.g., Eppendorf). The agar containing the recombinant viruses is then resuspended in a microcentrifuge tube containing 200 μl of Grace's medium and the suspension containing the recombinant baculovirus is used to infect Sf9 cells seeded in 35 mm dishes. Four days later the supernatants of these culture dishes are harvested and then they are stored at 4° C.

To verify the expression of the polypeptide, Sf9 cells are grown in Grace's medium supplemented with 10% heat-inactivated FBS. The cells are infected with the recombinant baculovirus containing the polynucleotide at a multiplicity of infection (“MOI”) of about 2. If radiolabeled proteins are desired, 6 hours later the medium is removed and is replaced with SF900 μl medium minus methionine and cysteine (available from Life Technologies Inc., Rockville, Md.). After 42 hours, 5 μCi of ³⁵S-methionine and 5 μCi ³⁵S-cysteine (available from Amersham) are added. The cells are further incubated for 16 hours and then are harvested by centrifugation. The proteins in the supernatant as well as the intracellular proteins are analyzed by SDS-PAGE followed by autoradiography (if radiolabeled).

Microsequencing of the amino acid sequence of the amino terminus of purified protein may be used to determine the amino terminal sequence of the produced protein.

Example 8 Expression of a Polypeptide in Mammalian Cells

The polypeptide of the present invention can be expressed in a mammalian cell. A typical mammalian expression vector contains a promoter element, which mediates the initiation of transcription of mRNA, a protein coding sequence, and signals required for the termination of transcription and polyadenylation of the transcript. Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and acceptor sites for RNA splicing. Highly efficient transcription is achieved with the early and late promoters from SV40, the long terminal repeats (LTRs) from Retroviruses, e.g., RSV, HTLVI, HIVI and the early promoter of the cytomegalovirus (CMV). However, cellular elements can also be used (e.g., the human actin promoter).

Suitable expression vectors for use in practicing the present invention include, for example, vectors such as pSVL and pMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146), pBCl₂MI (ATCC 67109), pCMVSport 2.0, and pCMVSport 3.0. Mammalian host cells that could be used include, human Hela, 293, H9 and Jurkat cells, mouse NIH3T3 and C127 cells, Cos 1, Cos 7 and CVI, quail QC1-3 cells, mouse L cells and Chinese hamster ovary (CHO) cells.

Alternatively, the polypeptide can be expressed in stable cell lines containing the polynucleotide integrated into a chromosome. The co-transfection with a selectable marker such as DHFR, gpt, neomycin, or hygromycin allows the identification and isolation of the transfected cells.

The transfected gene can also be amplified to express large amounts of the encoded protein. The DHFR (dihydrofolate reductase) marker is useful in developing cell lines that carry several hundred or even several thousand copies of the gene of interest. (See, e.g., Alt, F. W., et al., J. Biol. Chem. 253:1357-1370 (1978); Hamlin, J. L. and Ma, C., Biochem. et Biophys. Acta, 1097:107-143 (1990); Page, M. J. and Sydenham, M. A., Biotechnology 9:64-68 (1991)). Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279 (1991); Bebbington et al., Bio/Technology 10:169-175 (1992). Using these markers, the mammalian cells are grown in selective medium and the cells with the highest resistance are selected. These cell lines contain the amplified gene(s) integrated into a chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of proteins.

Derivatives of the plasmid pSV2-dhfr (ATCC Accession No. 37146), the expression vectors pC4 (ATCC Accession No. 209646) and pC6 (ATCC Accession No. 209647) contain the strong promoter (LTR) of the Rous Sarcoma Virus (Cullen et al., Molecular and Cellular Biology, 438-447 (March, 1985)) plus a fragment of the CMV-enhancer (Boshart et al., Cell 41:521-530 (1985)). Multiple cloning sites, e.g., with the restriction enzyme cleavage sites BamHI, XbaI and Asp718, facilitate the cloning of the gene of interest. The vectors also contain the 3′ intron, the polyadenylation and termination signal of the rat preproinsulin gene, and the mouse DHFR gene under control of the SV40 early promoter.

Specifically, the plasmid pC6, for example, is digested with appropriate restriction enzymes and then dephosphorylated using calf intestinal phosphates by procedures known in the art. The vector is then isolated from a 1% agarose gel.

A polynucleotide of the present invention is amplified according to the protocol outlined in Example 1. If a naturally occurring signal sequence is used to produce the polypeptide of the present invention, the vector does not need a second signal peptide. Alternatively, if a naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., International Publication No. WO 96/34891.)

The amplified fragment is isolated from a 1% agarose gel using a commercially available kit (“Geneclean,” BIO 101 Inc., La Jolla, Calif.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1% agarose gel.

The amplified fragment is then digested with the same restriction enzyme and purified on a 1% agarose gel. The isolated fragment and the dephosphorylated vector are then ligated with T4 DNA ligase. E. coli HB101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC6 using, for instance, restriction enzyme analysis.

Chinese hamster ovary cells lacking an active DHFR gene is used for transfection. Five μg of the expression plasmid pC6 or pC4 is cotransfected with 0.5 μg of the plasmid pSVneo using lipofectin (Felgner et al., supra). The plasmid pSV2-neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including G418. The cells are seeded in alpha minus MEM supplemented with 1 mg/ml G418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50 ng/ml of methotrexate plus 1 mg/ml G418. After about 10-14 days single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher concentrations of methotrexate (1 μM, 2 μM, 5 μM, 10 mM, 20 mM). The same procedure is repeated until clones are obtained which grow at a concentration of 100-200 μM. Expression of the desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reversed phase HPLC analysis.

Example 9 Protein Fusions

The polypeptides of the present invention are preferably fused to other proteins. These fusion proteins can be used for a variety of applications. For example, fusion of the present polypeptides to His-tag, HA-tag, protein A, IgG domains, and maltose binding protein facilitates purification. (See Example 5; see also EP A 394,827; Traunecker, et al., Nature 331:84-86 (1988)). Similarly, fusion to IgG-1, IgG-3, and albumin increases the halflife time in vivo. Nuclear localization signals fused to the polypeptides of the present invention can target the protein to a specific subcellular localization, while covalent heterodimer or homodimers can increase or decrease the activity of a fusion protein. Fusion proteins can also create chimeric molecules having more than one function. Finally, fusion proteins can increase solubility and/or stability of the fused protein compared to the non-fused protein. All of the types of fusion proteins described above can be made by modifying the following protocol, which outlines the fusion of a polypeptide to an IgG molecule, or the protocol described in Example 5.

Briefly, the human Fc portion of the IgG molecule can be PCR amplified, using primers that span the 5′ and 3′ ends of the sequence described below. These primers also should have convenient restriction enzyme sites that will facilitate cloning into an expression vector, preferably a mammalian expression vector.

For example, if pC4 (ATCC Accession No. 209646) is used, the human Fc portion can be ligated into the BamHI cloning site. Note that the 3′ BamHI site should be destroyed. Next, the vector containing the human Fc portion is re-restricted with BamHI, linearizing the vector, and a polynucleotide of the present invention, isolated by the PCR protocol described in Example 1, is ligated into this BamHI site. Note that the polynucleotide is cloned without a stop codon, otherwise a fusion protein will not be produced.

If the naturally occurring signal sequence is used to produce the polypeptide of the present invention, pC4 does not need a second signal peptide. Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., International Publication No. WO 96/34891.) Human IgG Fc region: GGGATCCGGAGCCCAAATCTTCTGACAAAACTCACACATGCCCACCGTGCCCAGCAC (SEQ ID NO: 1) CTGAATTCGAGGGTGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACTCCTGAGGTCACATGCGTGGTGGTGGACGTAAGCCACGAAGA CCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC AAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGT CCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGC CCTCCCAACCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACC ACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCT GACCTGCCTGGTCAAAGGCTTCTATCCAAGCGACATCGCCGTGGAGTGGGAGAGCAA TGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTC CTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC TCCCTGTCTCCGGGTAAATGAGTGCGACGGCCGCGACTCTAGAGGAT

Example 10 Production of an Antibody from a Polypeptide

a) Hybridoma Technology

The antibodies of the present invention can be prepared by a variety of methods. (See, Current Protocols, Chapter 2.) As one example of such methods, cells expressing a polypeptide of the present invention are administered to an animal to induce the production of sera containing polyclonal antibodies. In a preferred method, a preparation of a polypeptide of the present invention is prepared and purified to render it substantially free of natural contaminants. Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity.

Monoclonal antibodies specific for a polypeptide of the present invention are prepared using hybridoma technology (Kohler et al., Nature 256:495 (1975); Kohler et al., Eur. J. Immunol. 6:511 (1976); Kohler et al., Eur. J. Immunol. 6:292 (1976); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981)). In general, an animal (preferably a mouse) is immunized with a polypeptide of the present invention or, more preferably, with a secreted polypeptide-expressing cell. Such polypeptide-expressing cells are cultured in any suitable tissue culture medium, preferably in Barle's modified Eagle's medium supplemented with 10% fetal bovine serum (inactivated at about 56° C.), and supplemented with about 10 g/l of nonessential amino acids, about 1,000 U/ml of penicillin, and about 100 μg/ml of streptomycin.

The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; however, it is preferable to employ the parent myeloma cell line (SP20), available from the ATCC. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al. (Gastroenterology 80:225-232 (1981)). The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the polypeptide of the present invention.

Alternatively, additional antibodies capable of binding to a polypeptide of the present invention can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens, and therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, protein specific antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the polypeptide-specific antibody can be blocked by said polypeptide. Such antibodies comprise anti-idiotypic antibodies to the polypeptide-specific antibody and are used to immunize an animal to induce formation of further polypeptide-specific antibodies.

For in vivo use of antibodies in humans, an antibody is “humanized”. Such antibodies can be produced using genetic constructs derived from hybridoma cells producing the monoclonal antibodies described above. Methods for producing chimeric and humanized antibodies are known in the art and are discussed herein. (See, for review, Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., International Publication No. WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985)).

B) Isolation of Antibody Fragments Directed Against a Polypeptide of the Present Invention from a Library of scFvs

Naturally occurring V-genes isolated from human PBLs are constructed into a library of antibody fragments which contain reactivities against a polypeptide of the present invention to which the donor may or may not have been exposed (see e.g., U.S. Pat. No. 5,885,793 incorporated herein by reference in its entirety).

Rescue of the Library. A library of scFvs is constructed from the RNA of human PBLs as described in International Publication No. WO 92/01047. To rescue phage displaying antibody fragments, approximately 10⁹ E. coli harboring the phagemid are used to inoculate 50 ml of 2×TY containing 1% glucose and 100 μg/ml of ampicillin (2×TY-AMP-GLU) and grown to an O.D. of 0.8 with shaking. Five ml of this culture is used to inoculate 50 ml of 2×TY-AMP-GLU, 2×108 TU of delta gene 3 helper (M13 delta gene III, see International Publication No. WO 92/01047) are added and the culture incubated at 37° C. for 45 minutes without shaking and then at 37° C. for 45 minutes with shaking. The culture is centrifuged at 4000 r.p.m. for 10 min. and the pellet resuspended in 2 liters of 2×TY containing 100 μg/ml ampicillin and 50 ug/ml kanamycin and grown overnight. Phage are prepared as described in International Publication No. WO 92/01047.

M13 delta gene III is prepared as follows: M13 delta gene III helper phage does not encode gene III protein, hence the phage(mid) displaying antibody fragments have a greater avidity of binding to antigen. Infectious M13 delta gene III particles are made by growing the helper phage in cells harboring a pUC19 derivative supplying the wild type gene III protein during phage morphogenesis. The culture is incubated for 1 hour at 37° C. without shaking and then for a further hour at 37° C. with shaking. Cells are spun down (IEC-Centra 8,400 r.p.m. for 10 min), resuspended in 300 ml 2×TY broth containing 100 μg ampicillin/ml and 25 μg kanarnycin/ml (2×TY-AMP-KAN) and grown overnight, shaking at 37° C. Phage particles are purified and concentrated from the culture medium by two PEG-precipitations (Sambrook et al., 1990), resuspended in 2 ml PBS and passed through a 0.45 μm filter (Minisart NML; Sartorius) to give a final concentration of approximately 10¹³ transducing units/ml (ampicillin-resistant clones).

Panning of the Library. Immunotubes (Nunc) are coated overnight in PBS with 4 ml of either 100 μg/ml or 10 μg/ml of a polypeptide of the present invention. Tubes are blocked with 2% Marvel-PBS for 2 hours at 37° C. and then washed 3 times in PBS. Approximately 10¹³ TU of phage is applied to the tube and incubated for 30 minutes at room temperature tumbling on an over and under turntable and then left to stand for another 1.5 hours. Tubes are washed 10 times with PBS 0.1% Tween-20 and 10 times with PBS. Phage are eluted by adding 1 ml of 100 mM triethylamine and rotating 15 minutes on an under and over turntable after which the solution is immediately neutralized with 0.5 ml of 11.0M Tris-HCl, pH 7.4. Phage are then used to infect 10 ml of mid-log E. coli TG1 by incubating eluted phage with bacteria for 30 minutes at 37° C. The E. coli are then plated on TYE plates containing 1% glucose and 100 μg/ml ampicillin. The resulting bacterial library is then rescued with delta gene 3 helper phage as described above to prepare phage for a subsequent round of selection. This process is then repeated for a total of 4 rounds of affinity purification with tube-washing increased to 20 times with PBS, 0.1% Tween-20 and 20 times with PBS for rounds 3 and 4.

Characterization of Binders. Eluted phage from the 3rd and 4th rounds of selection are used to infect E. coli HB 2151 and soluble scFv is produced (Marks, et al., 1991) from single colonies for assay. ELISAs are performed with microtitre plates coated with either 10 pg/ml of the polypeptide of the present invention in 50 mM bicarbonate pH 9.6. Clones positive in ELISA are further characterized by PCR fingerprinting (see, e.g., International Publication No. WO 92/01047) and then by sequencing. These ELISA positive clones may also be further characterized by techniques known in the art, such as, for example, epitope mapping, binding affinity, receptor signal transduction, ability to block or competitively inhibit antibody/antigen binding, and competitive agonistic or antagonistic activity.

Example 11 Method of Determining Alterations in a Gene Corresponding to a Polynucleotide

RNA isolated from entire families or individual patients presenting with a hematopoietic or hematologic disease or disorder is isolated. cDNA is then generated from these RNA samples using protocols known in the art. (See, Sambrook.) The cDNA is then used as a template for PCR, employing primers surrounding regions of interest in SEQ ID NO:X; and/or the nucleotide sequence of the cDNA contained in ATCC Deposit No:Z. Suggested PCR conditions consist of 35 cycles at 95 degrees C. for 30 seconds; 60-120 seconds at 52-58 degrees C.; and 60-120 seconds at 70 degrees C., using buffer solutions described in Sidransky et al., Science 252:706 (1991).

PCR products are then sequenced using primers labeled at their 5′ end with T4 polynucleotide kinase, employing SequiTherm Polymerase (Epicentre Technologies). The intron-exon boundaries of selected exons is also determined and genomic PCR products analyzed to confirm the results. PCR products harboring suspected mutations are then cloned and sequenced to validate the results of the direct sequencing.

PCR products are cloned into T-tailed vectors as described in Holton et al., Nucleic Acids Research, 19:1156 (1991) and sequenced with T7 polymerase (United States Biochemical). Affected individuals are identified by mutations not present in unaffected individuals.

Genomic rearrangements are also observed as a method of determining alterations in a gene corresponding to a polynucleotide. Genomic clones isolated according to Example 2 are nick-translated with digoxigenindeoxy-uridine 5′-triphosphate (Boehringer Manheim), and FISH performed as described in Johnson et al., Methods Cell Biol. 35:73-99 (1991). Hybridization with the labeled probe is carried out using a vast excess of human cot-1 DNA for specific hybridization to the corresponding genomic locus.

Chromosomes are counterstained with 4,6-diamino-2-phenylidole and propidium iodide, producing a combination of C- and R-bands. Aligned images for precise mapping are obtained using a triple-band filter set (Chroma Technology, Brattleboro, Vt.) in combination with a cooled charge-coupled device camera (Photometrics, Tucson, Ariz.) and variable excitation wavelength filters. (Johnson et al., Genet. Anal. Tech. Appl., 8:75 (1991)). Image collection, analysis and chromosomal fractional length measurements are performed using the ISee Graphical Program System (Inovision Corporation, Durham, N.C.) Chromosome alterations of the genomic region hybridized by the probe are identified as insertions, deletions, and translocations. These alterations are used as a diagnostic marker for an associated disease.

Example 12 Method of Detecting Abnormal Levels of a Polypeptide in a Biological Sample

A polypeptide of the present invention can be detected in a biological sample, and if an increased or decreased level of the polypeptide is detected, this polypeptide is a marker for a particular phenotype. Methods of detection are numerous, and thus, it is understood that one skilled in the art can modify the following assay to fit their particular needs.

For example, antibody-sandwich ELISAs are used to detect polypeptides in a sample, preferably a biological sample. Wells of a microtiter plate are coated with specific antibodies, at a final concentration of 0.2 to 10 ug/ml. The antibodies are either monoclonal or polyclonal and are produced by the method described in Example 10. The wells are blocked so that non-specific binding of the polypeptide to the well is reduced.

The coated wells are then incubated for >2 hours at RT with a sample containing the polypeptide. Preferably, serial dilutions of the sample should be used to validate results. The plates are then washed three times with deionized or distilled water to remove unbound polypeptide.

Next, 50 ul of specific antibody-alkaline phosphatase conjugate, at a concentration of 25-400 ng, is added and incubated for 2 hours at room temperature. The plates are again washed three times with deionized or distilled water to remove unbound conjugate.

Add 75 ul of 4-methylumbelliferyl phosphate (MUP) or p-nitrophenyl phosphate (NPP) substrate solution to each well and incubate 1 hour at room temperature. Measure the reaction by a microtiter plate reader. Prepare a standard curve, using serial dilutions of a control sample, and plot polypeptide concentration on the X-axis (log scale) and fluorescence or absorbance of the Y-axis (linear scale). Interpolate the concentration of the polypeptide in the sample using the standard curve.

Example 13 Formulation

The invention also provides methods of preventing, treating and/or ameliorating a hematopoietic and hematologic disease or disorder by administration to a subject of an effective amount of a Therapeutic. By therapeutic is meant polynucleotides or polypeptides of the invention (including fragments and variants), agonists or antagonists thereof, and/or antibodies thereto, in combination with a pharmaceutically acceptable carrier type (e.g., a sterile carrier).

The Therapeutic will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with the Therapeutic alone), the site of delivery, the method of administration, the scheduling of administration, and other factors known to practitioners. The “effective amount” for purposes herein is thus determined by such considerations.

As a general proposition, the total pharmaceutically effective amount of the Therapeutic administered parenterally per dose will be in the range of about 1 ug/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day for the hormone. If given continuously, the Therapeutic is typically administered at a dose rate of about 1 ug/kg/hour to about 50 ug/kg/hour, either by 14 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed. The length of treatment needed to observe changes and the interval following treatment for responses to occur appears to vary depending on the desired effect.

Therapeutics can be are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

Therapeutics of the invention are also suitably administered by sustained-release systems. Suitable examples of sustained-release Therapeutics are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

Therapeutics of the invention are also suitably administered by sustained-release systems. Suitable examples of sustained-release Therapeutics include suitable polymeric materials (such as, for example, semi-permeable polymer matrices in the form of shaped articles, e.g., films, or mirocapsules), suitable hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, and sparingly soluble derivatives (such as, for example, a sparingly soluble salt).

Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547-556 (1983)), poly (2-hydroxyethyl methacrylate) (Langer et al., J. Biomed. Mater. Res. 15:167-277 (1981), and Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinyl acetate (Langer et al., Id.) or poly-D-(−)-3-hydroxybutyric acid (EP 133,988).

In a preferred embodiment, polypeptide, polynucleotide, and antibody compositions of the invention are formulated in a biodegradable, polymeric drug delivery system, for example as described in U.S. Pat. Nos. 4,938,763; 5,278,201; 5,278,202; 5,324,519; 5,340,849; and 5,487,897 and in International Publication Numbers WO01/35929, WO00/24374, and WO00/06117 which are hereby incorporated by reference in their entirety. In specific preferred embodiments the polypeptide, polynucleotide, and antibody compositions of the invention are formulated using the ATRIGEL® Biodegradable System of Atrix Laboratories, Inc. (Fort Collins, Colo.).

Examples of biodegradable polymers which can be used in the formulation of polypeptide, polynucleotide, and antibody compositions, include but are not limited to, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures of the above materials. The preferred polymers are those that have a lower degree of crystallization and are more hydrophobic. These polymers and copolymers are more soluble in the biocompatible solvents than the highly crystalline polymers such as polyglycolide and chitin which also have a high degree of hydrogen-bonding. Preferred materials with the desired solubility parameters are the polylactides, polycaprolactones, and copolymers of these with glycolide in which there are more amorphous regions to enhance solubility. In specific preferred embodiments, the biodegradable polymers which can be used in the formulation of polypeptide, polynucleotide, and antibody compositions are poly(lactide-co-glycolides). Polymer properties such as molecular weight, hydrophobicity, and lactide/glycolide ratio may be modified to obtain the desired polypeptide, polynucleotide, or antibody release profile (See, e.g., Ravivarapu et al., Journal of Pharmaceutical Sciences 89:732-741 (2000), which is hereby incorporated by reference in its entirety).

It is also preferred that the solvent for the biodegradable polymer be non-toxic, water miscible, and otherwise biocompatible. Examples of such solvents include, but are not limited to, N-methyl-2-pyrrolidone, 2-pyrrolidone, C2 to C6 alkanols, C1 to C15 alchohols, dils, triols, and tetraols such as ethanol, glycerine propylene glycol, butanol; C3 to C15 alkyl ketones such as acetone, diethyl ketone and methyl ethyl ketone; C3 to C15 esters such as methyl acetate, ethyl acetate, ethyl lactate; alkyl ketones such as methyl ethyl ketone, C1 to C15 amides such as dimethylformamide, dimethylacetamide and caprolactam; C3 to C20 ethers such as tetrahydrofuran, or solketal; tweens, triacetin, propylene carbonate, decylmethylsulfoxide, dimethyl sulfoxide, oleic acid, 1-dodecylazacycloheptan-2-one, Other preferred solvents are benzyl alchohol, benzyl benzoate, dipropylene glycol, tributyrin, ethyl oleate, glycerin, glycofural, isopropyl myristate, isopropyl palmitate, oleic acid, polyethylene glycol, propylene carbonate, and triethyl citrate. The most preferred solvents are N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triacetin, and propylene carbonate because of the solvating ability and their compatibility.

Additionally, formulations comprising polypeptide, polynucleotide, and antibody compositions and a biodegradable polymer may also include release-rate modification agents and/or pore-forming agents. Examples of release-rate modification agents include, but are not limited to, fatty acids, triglycerides, other like hydrophobic compounds, organic solvents, plasticizing compounds and hydrophilic compounds. Suitable release rate modification agents include, for example, esters of mono-, di-, and tricarboxylic acids, such as 2-ethoxyethyl acetate, methyl acetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, glycerol triacetate, di(n-butyl) sebecate, and the like; polyhydroxy alcohols, such as propylene glycol, polyethylene glycol, glycerin, sorbitol, and the like; fatty acids; triesters of glycerol, such as triglycerides, epoxidized soybean oil, and other epoxidized vegetable oils; sterols, such as cholesterol; alcohols, such as C.sub.6-C.sub.12 alkanols, 2-ethoxyethanol. The release rate modification agent may be used singly or in combination with other such agents. Suitable combinations of release rate modification agents include, but are not limited to, glycerin/propylene glycol, sorbitol/glycerine, ethylene oxide/propylene oxide, butylene glycol/adipic acid, and the like. Preferred release rate modification agents include, but are not limited to, dimethyl citrate, triethyl citrate, ethyl heptanoate, glycerin, and hexanediol. Suitable pore-forming agents that may be used in the polymer composition include, but are not limited to, sugars such as sucrose and dextrose, salts such as sodium chloride and sodium carbonate, polymers such as hydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol, and polyvinylpyrrolidone. Solid crystals that will provide a defined pore size, such as salt or sugar, are preferred.

In specific preferred embodiments the polypeptide, polynucleotide, and antibody compositions of the invention are formulated using the BEMA™ BioErodible Mucoadhesive System, MCA™ MucoCutaneous Absorption System, SMP™ Solvent MicroParticle System, or BCP™ BioCompatible Polymer System of Atrix Laboratories, Inc. (Fort Collins, Colo.).

Sustained-release Therapeutics also include liposomally entrapped Therapeutics of the invention (see generally, Langer, Science 249:1527-1533 (1990); Treat et al., in Liposoines in tle Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 317-327 and 353-365 (1989)). Liposomes containing the Therapeutic are prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal Therapeutic.

In yet an additional embodiment, the Therapeutics of the invention are delivered by way of a pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)).

Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).

For parenteral administration, in one embodunent, the Therapeutic is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to the Therapeutic.

Generally, the formulations are prepared by contacting the Therapeutic uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.

The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, manose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.

The Therapeutic is typically formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mg/ml, at a pH of about 3 to 8. It will be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of polypeptide salts.

Any pharmaceutical used for therapeutic administration can be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutics generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

Therapeutics ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-ml vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous Therapeutic solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized Therapeutic using bacteriostatic Water-for-Injection.

The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the Therapeutics of the invention. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. In addition, the Therapeutics may be employed in conjunction with other therapeutic compounds.

The Therapeutics of the invention may be administered alone or in combination with adjuvants. Adjuvants that may be administered with the Therapeutics of the invention include, but are not limited to, alum, alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21 (Genentech, Inc.), BCG (e.g., THERACYS®), MPL and nonviable prepartions of Corynebacterium parvum. In a specific embodiment, Therapeutics of the invention are administered in combination with alu In another specific embodiment, Therapeutics of the invention are administered in combination with QS-21. Further adjuvants that may be administered with the Therapeutics of the invention include, but are not limited to, Monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18, CRL1005, Aluminum salts, MF-59, and Virosomal adjuvant technology. Vaccines that may be administered with the Therapeutics of the invention include, but are not limited to, vaccines directed toward protection against MMR (measles, mumps, rubella), polio, varicella, tetanus/diptheria, hepatitis A, hepatitis B, haemophilus influenzae B, whooping cough, pneumonia, influenza, Lyme's Disease, rotavirus, cholera, yellow fever, Japanese encephalitis, poliomyelitis, rabies, typhoid fever, and pertussis. Combinations may be administered either concomitantly, e.g., as an admixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and also procedures in which the combined agents are administered separately but simultaneously, e.g., as through separate intravenous lines into the same individual. Administration “in combination” further includes the separate administration of one of the compounds or agents given first, followed by the second.

The Therapeutics of the invention may be administered alone or in combination with other therapeutic agents. Therapeutic agents that may be administered in combination with the Therapeutics of the invention, include but not limited to, chemotherapeutic agents, antibiotics, steroidal and non-steroidal anti-inflammatories, conventional immunotherapeutic agents, and/or therapeutic treatments described below. Combinations may be administered either concomitantly, e.g., as an admixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and also procedures in which the combined agents are administered separately but simultaneously, e.g., as through separate intravenous lines into the same individual. Administration “in combination” further includes the separate administration of one of the compounds or agents given first, followed by the second.

In one embodiment, the Therapeutics of the invention are administered in combination with an anticoagulant. Anticoagulants that may be administered with the compositions of the invention include, but are not limited to, heparin, low molecular weight heparin, warfarin sodium (e.g., COUMADIN®), dicumarol, 4-hydroxycoumarin, anisindione (e.g., MIRADON™), acenocoumarol (e.g., nicoumalone, SINTHROME™), indan-1,3-dione, phenprocoumon (e.g., MARCUMAR™), ethyl biscoumacetate (e.g., TROMEXAN™), and aspirin. In a specific embodiment, compositions of the invention are administered in combination with heparin and/or warfarin. In another specific embodiment, compositions of the invention are administered in combination with warfarin. In another specific embodiment, compositions of the invention are administered in combination with warfarin and aspirin. In another specific embodiment, compositions of the invention are administered in combination with heparin. In another specific embodiment, compositions of the invention are administered in combination with heparin and aspirin.

In another embodiment, the Therapeutics of the invention are administered in combination with thrombolytic drugs. Thrombolytic drugs that may be administered with the compositions of the invention include, but are not limited to, plasminogen, lys-plasminogen, alpha2-antiplasmin, streptokinae (e.g., KABIKINASE™), antiresplace (e.g., EMINASE™), tissue plasminogen activator (t-PA, altevase, ACTIVASE™), urokinase (e.g., ABBOKINASE™), sauruplase, (Prourokinase, single chain urokinase), and aminocaproic acid (e.g., AMICAR™). In a specific embodiment, compositions of the invention are administered in combination with tissue plasminogen activator and aspirin.

In another embodiment, the Therapeutics of the invention are administered in combination with antiplatelet drugs. Antiplatelet drugs that may be administered with the compositions of the invention include, but are not limited to, aspirin, dipyridamole (e.g., PERSANTINE™), and ticlopidine (e.g., TICLID™).

In specific embodiments, the use of anti-coagulants, thrombolytic and/or antiplatelet drugs in combination with Therapeutics of the invention is contemplated for the detection, prevention, diagnosis, prognostication, treatment, and/or amelioration of thrombosis, arterial thrombosis, venous thrombosis, thromboembolism, pulmonary embolism, atherosclerosis, myocardial infarction, transient ischemic attack, unstable angina. In specific embodiments, the use of anticoagulants, thrombolytic drugs and/or antiplatelet drugs in combination with Therapeutics of the invention is contemplated for the prevention of occulsion of saphenous grafts, for reducing the risk of periprocedural thrombosis as might accompany angioplasty procedures, for reducing the risk of stroke in patients with atrial fibrillation including nonrheumatic atrial fibrillation, for reducing the risk of embolism associated with mechanical heart valves and or mitral valves disease. Other uses for the therapeutics of the invention, alone or in combination with antiplatelet, anticoagulant, and/or thrombolytic drugs, include, but are not limited to, the prevention of occlusions in extracorporeal devices (e.g., intravascular canulas, vascular access shunts in hemodialysis patients, hemodialysis machines, and cardiopulmonary bypass machines).

In certain embodiments, Therapeutics of the invention are administered in combination with antiretroviral agents, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and/or protease inhibitors (PIs). NRTIs that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, RETROVIR™ (zidovudine/AZT), VIDEX™ (didanosine/ddI), HIVID™ (zalcitabinelddC), ZERIT™ (stavudine/d4T), EPIVIR™ (lanivudine/3TC), and COMBIVIR™ (zidovudine/lamivudine). NNRTIs that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, VTRAMUNE™ (nevirapine), RESCRIPTOR™ (delavirdine), and SUSTIVA™ (efavirenz). Protease inhibitors that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, CRIXIVAN™ (indinavir), NORVIR™ (ritonavir), INVIRASE™ (saquinavir), and VIRACEPT™ (nelfinavir). In a specific embodiment, antiretroviral agents, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and/or protease inhibitors may be used in any combination with Therapeutics of the invention to treat AIDS and/or to prevent or treat HIV infection.

Additional NRTIs include LODENOSINE™ (F-ddA; an acid-stable adenosine NRTI; Triangle/Abbott; COVIRACIL™ (entricitabine/FTC; structurally related to lamivudine (3TC) but with 3- to 10-fold greater activity in vitro; Triangle/Abbott); dOTC (BCH-10652, also structurally related to lamivudine but retains activity against a substantial proportion of lamivudine-resistant isolates; Biochem Pharma); Adefovir (refused approval for anti-HIV therapy by FDA; Gilead Sciences); PREVEON® (Adefovir Dipivoxil, the active prodrug of adefovir, its active form is PMEA-pp); TENOFOVIR” (bis-POC PMPA, a PMPA prodrug; Gilead); DAPD/DXG (active metabolite of DAPD; Triangle/Abbott); D-D4FC (related to 3TC, with activity against AZT/3TC-resistant virus); GW420867X (Glaxo Wellcome); ZIAGEN™ (abacavir/159U89; Glaxo Wellcome Inc.); CS-87 (3′azido-2′,3′-dideoxyuridine; WO 99/66936); and S-acyl-2-thioethyl (SATE)-bearing prodrug forms of β-L-FD4C and β-L-FddC (WO 98/17281).

Additional NNRTIs include COACTINON™ (Emivirine/MKC-442, potent NNRTI of the HEPT class; Triangle/Abbott); CAPRAVIRINE™ (AG-1549/S-1153, a next generation NNRTI with activity against viruses containing the K103N mutation; Agouron); PNU-142721 (has 20- to 50-fold greater activity than its predecessor delavirdine and is active against K103N mutants; Pharmacia & Upjohn); DPC-961 and DPC-963 (second-generation derivatives of efavirenz, designed to be active against viruses with the K103N mutation; DuPont); GW-420867× (has 25-fold greater activity than HBY097 and is active against K103N mutants; Glaxo Wellcome); CALANOLIDE A (naturally occurring agent from the latex tree; active against viruses containing either or both the Y181C and K103N mutations); and Propolis (WO 99/49830).

Additional protease inhibitors include LOPINAVIR™ (ABT378/r; Abbott Laboratories); BMS-232632 (an azapeptide; Bristol-Myres Squibb); TIPRANAVIR™ (PNU-140690, a non-peptic dihydropyrone; Phanmacia & Upjohn); PD-178390 (a nonpeptidic dihydropyrone; Parke-Davis); BMS 232632 (an azapeptide; Bristol-Myers Squibb); L-756,423 (an indinavir analog; Merck); DMP-450 (a cyclic urea compound; Avid & DuPont); AG-1776 (a peptidomimetic with in vitro activity against protease inhibitor-resistant viruses; Agouron); VX-175/GW-433908 (phosphate prodrug of amprenavir; Vertex & Glaxo Welcome); CGP61755 (Ciba); and AGENERASE™ (amprenavir; Glaxo Wellcome Inc.).

Additional antiretroviral agents include fusion inhibitors/gp41 binders. Fusion inhibitors/gp41 binders include T-20 (a peptide from residues 643-678 of the HIV gp41 transmembrane protein ectodomain which binds to gp41 in its resting state and prevents transformation to the fusogenic state; Trimeris) and T-1249 (a second-generation fusion inhibitor, Trimeris).

Additional antiretroviral agents include fusion inhibitors/chemokine receptor antagonists. Fusion inhibitors/chemokine receptor antagonists include CXCR4 antagonists such as AMD 3100 (a bicyclam), SDF-1 and its analogs, and ALX40-4C (a cationic peptide), T22 (an 18 amino acid peptide; Trimeris) and the T22 analogs T134 and T140; CCR5 antagonists such as RANTES (9-68), AOP-RANTES, NNY-RANTES, and TAK-779; and CCR5/CXCR4 antagonists such as NSC 651016 (a distamycin analog). Also included are CCR2B, CCR3, and CCR6 antagonists. Chemokine recpetor agonists such as RANTES, SDF-1, MIP-1α, MIP-1β, etc., may also inhibit fusion.

Additional antiretroviral agents include integrase inhibitors. Integrase inhibitors include dicaffeoylquinic (DFQA) acids; Lchicoric acid (a dicaffeoyltartaric (DCTA) acid); quinalizari (QLC) and related anthraquinones; ZINTEVIR™ (AR 177, an oligonucleotide that probably acts at cell surface rather than being a true integrase inhibitor, Arondex); and naphthols such as those disclosed in WO 98/50347.

Additional antiretroviral agents include hydroxyurea-like compunds such as BCX-34 (a purine nucleoside phosphorylase inhibitor; Biocryst); ribonucleotide reductase inhibitors such as DIDOX™ (Molecules for Health); inosine monophosphate dehydrogenase (IMPDH) inhibitors sucha as VX-497 (Vertex); and mycopholic acids such as CellCept (mycophenolate mofetil; Roche).

Additional antiretroviral agents include inhibitors of viral integrase, inhibitors of viral genome nuclear translocation such as arylene bis(methylketone) compounds; inhibitors of HIV entry such as AOP-RANTES, NNY-RANTES, RANTES-IgG fusion protein, soluble complexes of RANTES and glycosaminoglycans (GAG), and AMD-3100; nucleocapsid zinc finger inhibitors such as dithiane compounds; targets of HIV Tat and Rev; and pharmacoenhancers such as ABT-378.

Other antiretroviral therapies and adjunct therapies include cytokines and lymphokines such as MIP-1α, MIP-1β, SDF-1α, IL-2, PROLEUKIN™ (aldesleukin/L2-7001; Chiron), IL-4, IL-10, IL-12, and IL-13; interferons such as IFN-α2a; antagonists of TNFs, NFκB, GM-CSF, M-CSF, and IL-10; agents that modulate immune activation such as cyclosporin and prednisone; vaccines such as Remune™ (HIV Immunogen), APL 400-003 (Apollon), recombinant gp120 and fragments, bivalent (B/E) recombinant envelope glycoprotein, rgp120CM235, MN rgp120, SF-2 rgp120, gp120/soluble CD4 complex, Delta JR-FL protein, branched synthetic peptide derived from discontinuous gp120 C3/C4 domain, fusion-competent immunogens, and Gag, Pol, Nef, and Tat vaccines; gene-based therapies such as genetic suppressor elements (GSES; WO 98/54366), and intrakines (genetically modified CC chemokines targetted to the ER to block surface expression of newly synthesized CCR5 (Yang et al., PNAS 94:11567-72 (1997); Chen et al., Nat. Med. 3:1110-16 (1997)); antibodies such as the anti-CXCR4 antibody 12G5, the anti-CCR5 antibodies 2D7, 5C7, PA8, PA9, PA10, PA11, PA12, and PA14, the anti-CD4 antibodies Q4120 and RPA-T4, the anti-CCR3 antibody 7B11, the anti-gp120 antibodies 17b, 48d, 447-52D, 257-D, 268-D and 50.1, anti-Tat antibodies, anti-TNF-α antibodies, and monoclonal antibody 33A; aryl hydrocarbon (AH) receptor agonists and antagonists such as TCDD, 3,3′,4,4′,5-pentachlorobiphenyl, 3,3′,4,4′-tetrachlorobiphenyl, and α-naphthoflavone (WO 98/30213); and antioxidants such as γ-L-glutamyl-L-cysteine ethyl ester (γ-GCE; WO 99/56764).

In a further embodiment, the Therapeutics of the invention are administered in combination with an antiviral agent. Antiviral agents that may be administered with the Therapeutics of the invention include, but are not limited to, acyclovir, ribavirin, amantadine, and remantidine.

In other embodiments, Therapeutics of the invention may be administered in combination with anti-opportunistic infection agents. Anti-opportunistic agents that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDNE™ ATOVAQUONE™, ISONIAZID™, RIFAMPIN™, PYRAZINAMDE™, ETHAMUTOL™, RIFABUTIN™, CLARITHROMYCN™, AZITHROMYCIN™, GANCICLOVIR™, FOSCARNET™, CIDOFOVIR™, FLUCONAZOLE™, ITRACONAZOLE™, KETOCONAZOLE™, ACYCLOVIR™, FAMCICOLVIR™, PYRIMETHAMINE™, LEUCOVORINE™, NEUPOGEN™ (filgrastim/G-CSF), and LEUKINE™ (sargramostim/GM-CSF). In a specific embodiment, Therapeutics of the invention are used in any combination with TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDINE™, and/or ATOVAQUONE™ to prophylactically treat or prevent an opportunistic Pneumocystis carinii pneumonia infection. In another specific embodiment, Therapeutics of the invention are used in any combination with ISONIAZD™, RIAMPAN™, PYRAZINAMIDE™, and/or ETHAMBUTOL™ to prophylactically treat or prevent an opportunistic Mycobacterium avium complex infection. In another specific embodiment, Therapeutics of the invention are used in any combination with RIFABUTIN™, CLARITHROMYCIN™, and/or AZITHROMYCIN™ to prophylactically treat or prevent an opportunistic Mycobacterium tuberculosis infection. In another specific embodiment, Therapeutics of the invention are used in any combination with GANCICLOVIR™, FOSCARNET™, and/or CIDOPOVIR™ to prophylactically treat or prevent an opportunistic cytomegalovirus infection. In another specific embodiment, Therapeutics of the invention are used in any combination with FLUCONAZOLE™, ITRACONAZOLE™, and/or KETOCONAZOLE™ to prophylactically treat or prevent an opportunistic fungal infection. In another specific embodiment, Therapeutics of the invention are used in any combination with ACYCLOVIR™ and/or FAMCICOLVIR™ to prophylactically treat or prevent an opportunistic herpes simplex virus type I and/or type II infection. In another specific embodiment, Therapeutics of the invention are used in any combination with PYRIMETHAMINE™ and/or LEUCOVORIN™ to prophylactically treat or prevent an opportunistic Toxoplasma gondii infection. In another specific embodiment, Therapeutics of the invention are used in any combination with LEUCOVORIN™ and/or NEUPOGEN™ to prophylactically treat or prevent an opportunistic bacterial infection.

In a further embodiment, the Therapeutics of the invention are administered in combination with an antibiotic agent. Antibiotic agents that may be administered with the Therapeutics of the invention include, but are not limited to, amoxicillin, beta-lactamases, aminoglycosides, beta-lactam (glycopeptide), beta-lactamases, Clindamycin, chloramphenicol, cephalosporins, ciprofloxacin, erythromycin, fluoroquinolones, macrolides, metronidazole, penicillins, quinolones, rapamycin, rifampin, streptomycin, sulfonamide, tetracyclines, trimethoprim, trimethoprim-sulfamethoxazole, and vancomycin.

In other embodiments, the Therapeutics of the invention are administered in combination with immunestimulants. Immunostimulants that may be administered in combination with the Therapeutics of the invention include, but are not limited to, levamisole (e.g., ERGAMISOL™), isoprinosine (e.g. INOSIPLEX™), interferons (e.g. interferon alpha), and interleukins (e.g., IL-2).

In other embodiments, Therapeutics of the invention are administered in combination with immunosuppressive agents. Immunosuppressive agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to, steroids, cyclosporine, cyclosporine analogs, cyclophosphamide methylprednisone, prednisone, azathioprine, FK-506, 15-deoxyspergualin, and other immunosuppressive agents that act by suppressing the function of responding T cells. Other immunosuppressive agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to, prednisolone, methotrexate, thalidomide, methoxsalen, rapamycin, leflunomide, mizoribine (BREDNIN™), brequinar, deoxyspergualin, and azaspirane (SKF 105685), ORTHOCLONE OKT® 3 (muromonab-CD3), SANDIMMUNE™, NEORAL™, SANGDYA™ (cyclosporine), PROGRAF® (FK506, tacrolimus), CELLCEPT® (mycophenolate motefil, of which the active metabolite is mycophenolic acid), IMURAN™ (azathioprine), glucocorticosteroids, adrenocortical steroids such as DELTASONE™ (prednisone) and HYDELTRASOL™ (prednisolone), FOLEX™ and MEXATE™ (methotrxate), OXSORALEN-ULTRA™ (methoxsalen) and RAPAMUNE™ (sirolimus). In a specific embodiment, immunosuppressants may be used to prevent rejection of organ or bone marrow transplantation.

In an additional embodiment, Therapeutics of the invention are administered alone or in combination with one or more intravenous immune globulin preparations. Intravenous immune globulin preparations that may be administered with the Therapeutics of the invention include, but not limited to, GAMMAR™, IVEEGAM™, SANDOGLOBULIN™, GAMMAGARD S/D™, ATGAM™ (antithymocyte glubulin), and GAMIMUNE™. In a specific embodiment, Therapeutics of the invention are administered in combination with intravenous immune globulin preparations in transplantation therapy (e.g., bone marrow transplant).

In certain embodiments, the Therapeutics of the invention are administered alone or in combination with an anti-inflammatory agent Anti-inflammatory agents that may be administered with the Therapeutics of the invention include, but are not limited to, corticosteroids (e.g. betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone), nonsteroidal anti-inflammatory drugs (e.g., diclofenac, diflunisal, etodolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tenoxicam, tiaprofenic acid, and tolmetin.), as well as antihistamines, aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, and tenidap.

In an additional embodiment, the compositions of the invention are administered alone or in combination with an anti-angiogenic agent. Anti-angiogenic agents that may be administered with the compositions of the invention include, but are not limited to, Angiostatin (Entremed, Rockville, Md.), Troponin-1 (Boston Life Sciences, Boston, Mass.), anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel (Taxol), Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, VEGL Plasminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, and various forms of the lighter “d group” transition metals.

Lighter “d group” transition metals include, for example, vanadium, molybdenum, tungsten, titanium, niobium, and tantalum species. Such transition metal species may form transition metal complexes. Suitable complexes of the above-mentioned transition metal species include oxo transition metal complexes.

Representative examples of vanadium complexes include oxo vanadium complexes such as vanadate and vanadyl complexes. Suitable vanadate complexes include metavanadate and orthovanadate complexes such as, for example, ammonium metavanadate, sodium metavanadate, and sodium orthovanadate. Suitable vanadyl complexes include, for example, vanadyl acetylacetonate and vanadyl sulfate including vanadyl sulfate hydrates such as vanadyl sulfate mono- and trihydrates.

Representative examples of tungsten and molybdenum complexes also include oxo complexes. Suitable oxo tungsten complexes include tungstate and tungsten oxide complexes. Suitable tungstate complexes include ammonium tungstate, calcium tungstate, sodium tungstate dihydrate, and tungstic acid. Suitable tungsten oxides include tungsten (IV) oxide and tungsten (VI) oxide. Suitable oxo molybdenum complexes include molybdate, molybdenum oxide, and molybdenyl complexes. Suitable molybdate complexes include ammonium molybdate and its hydrates, sodium molybdate and its hydrates, and potassium molybdate and its hydrates. Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum (VI) oxide, and molybdic acid. Suitable molybdenyl complexes include, for example, molybdenyl acetylacetonate. Other suitable tungsten and molybdenum complexes include hydroxo derivatives derived from, for example, glycerol, tartaric acid, and sugars.

A wide variety of other anti-angiogenic factors may also be utilized within the context of the present invention. Representative examples include, but are not limited to, platelet factor 4; protamine sulphate; sulphated chitin derivatives (prepared from queen crab shells), (Murata et al., Cancer Res. 51:22-26, (1991)); Sulphated Polysaccharide Peptidoglycan Complex (SP-PG) (the function of this compound may be enhanced by the presence of steroids such as estrogen, and tamoxifen citrate); Staurosporine; modulators of matrix metabolism, including for example, proline analogs, cishydroxyproline, d,L-3,4-dehydroproline, Thiaproline, alpha,alpha-dipyridyl, aminopropionitrile fumarate; 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Methotrexate; Mitoxantrone; Heparin; Interferons; 2 Macroglobulin-serum; ChIMP-3 (Pavloff et al., J. Bio. Chem. 267:17321-17326, (1992)); Chymostatin (Tomkinson et al., Biochem J. 286:475-480, (1992)); Cyclodextrin Tetradecasulfate; Eponemycin; Camptothecin; Fumagillin (Ingber et al., Nature 348:555-557, (1990)); Gold Sodium Thiomalate (“GST”; Matsubara and Ziff, J. Clin. Invest. 79:1440-1446, (1987)); anticollagenase-serum; alpha2-antiplasmin (Holmes et al., J. Biol. Chern. 262(4):1659-1664, (1987)); Bisantrene (National Cancer Institute); Lobenzarit disodium (N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”; (Takeuchi et al., Agents Actions 36:312-316, (1992)); and metalloproteinase inhibitors such as BB94.

Additional anti-angiogenic factors that may also be utilized within the context of the present invention include Thalidomide, (Celgene, Warren, N.J.); Angiostatic steroid; AGM-1470 (H. Brem and J. Folkman J Pediatr. Surg. 28:445-51 (1993)); an integrin alpha v beta 3 antagonist (C. Storgard et al., J Clin. Invest. 103:47-54 (1999)); carboxynaminolmidazole; Carboxyamidotriazole (CAI) (National Cancer Institute, Bethesda, Md.); Conbretastatin A-4 (CA4P) (OXiGENE, Boston, Mass.); Squalamine (Magainin Pharmaceuticals, Plymouth Meeting, Pa.); TNP-470, (Tap Pharmaceuticals, Deerfield, Ill.); ZD-0101 AstraZeneca (London, UK); APRA (CT2584); Benefin, Byrostatin-1 (SC339555); CGP-41251 (PKC 412); CM101; Dexrazoxane (ICRF187); DMXAA; Endostatin; Flavopridiol; Genestein; GTE; ImmTher; Iressa (ZD1839); Octreotide (Somatostatin); Panretin; Penacillamine; Photopoint; PI-88; Prinomastat (AG-3340) Purlytin; Suradista (FCE26644); Tamoxifen (Nolvadex); Tazarotene; Tetrathiomolybdate; Xeloda (Capecitabine); and 5-Fluorouracil.

Anti-angiogenic agents that may be administed in combination with the compounds of the invention may work through a variety of mechanisms including, but not limited to, inhibiting proteolysis of the extracellular matrix, blocking the function of endothelial cell-extracellular matrix adhesion molecules, by antagonizing the function of angiogenesis inducers such as growth factors, and inhibiting integrin receptors expressed on proliferating endothelial cells. Examples of anti-angiogenic inhibitors that interfere with extracellular matrix proteolysis and which may be administered in combination with the compositons of the invention include, but are not lmited to, AG-3340 (Agouron, La Jolla, Calif.), BAY-12-9566 (Bayer, West Haven, Conn.), BMS-275291 (Bristol Myers Squibb, Princeton, N.J.), CGS-27032A (Novartis, East Hanover, N.J.), Marimastat (British Biotech, Oxford, UK), and Metastat (Aeterna, St-Foy, Quebec). Examples of anti-angiogenic inhibitors that act by blocking the function of endothelial cell-extracellular matrix adhesion molecules and which may be administered in combination with the compositons of the invention include, but are not limited to, EMD-121974 (Merck KcgaA Darmstadt, Germany) and Vitaxin (xsys, La Jolla, Calif./Medimmune, Gaithersburg, Md.). Examples of anti-angiogenic agents that act by directly antagonizing or inhibiting angiogenesis inducers and which may be administered in combination with the compositons of the invention include, but are not lmited to, Angiozyme (Ribozyme, Boulder, Colo.), Anti-VEGF antibody (Genentech, S. San Francisco, Calif.), PTK-787/ZK-225846 (Novartis, Basel, Switzerland), SU-101 (Sugen, S. San Francisco, Calif.), SU-5416 (Sugen/Pharmacia Upjohn, Bridgewater, N.J.), and SU-6668 (Sugen). Other anti-angiogenic agents act to indirectly inhibit angiogenesis. Examples of indirect inhibitors of angiogenesis which may be administered in combination with the compositons of the invention include, but are not limited to, IM-862 (Cytran, Kirkland, Wash.), Interferon-alpha, IL-12 (Roche, Nutley, N.J.), and Pentosan polysulfate (Georgetown University, Washington, D.C.).

In particular embodiments, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of an autoimmune disease, such as for example, an autoimmune disease described herein.

In a particular embodiment, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of arthritis. In a more particular embodiment, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of rheumatoid arthritis.

In another embodiment, the polynucleotides encoding a polypeptide of the present invention are administered in combination with an angiogenic protein, or polynucleotides encoding an angiogenic protein. Examples of angiogenic proteins that may be administered with the compositions of the invention include, but are not limited to, acidic and basic fibroblast growth factors, VEGF-1, VEGF-2, VEGF-3, epidermal growth factor alpha and beta, platelet-derived endothelial cell growth factor, platelet-derived growth factor, tumor necrosis factor alpha, hepatocyte growth factor, insulin-like growth factor, colony stimulating factor, macrophage colony stimulating factor, granulocyte/macrophage colony stimulating factor, and nitric oxide synthase.

In additional embodiments, compositions of the invention are administered in combination with a chemotherapeutic agent. Chemotherapeutic agents that may be administered with the Therapeutics of the invention include, but are not limited to alkylating agents such as nitrogen mustards (for example, Mechlorethamine, cyclophosphamide, Cyclophosphamide Ifosfamide, Melphalan (L-sarcolysin), and Chlorambucil), ethylenimines and methylmelamines (for example, Hexamethylmelamine and Thiotepa), alkyl sulfonates (for example, Busulfan), nitrosoureas (for example, Carmustine (BCNU), Lomustine (CCNU), Semustine (methyl-CCNU), and Streptozocin (streptozotocin)), triazenes (for example, Dacarbazine (DTIC; dimethyltriazenoimidazolecarboxamide)), folic acid analogs (for example, Methotrexate (amethopterin)), pyrimidine analogs (for example, Fluorouacil (5-fluorouracil; 5-FU), Floxuridine (fluorodeoxyuridine; FudR), and Cytarabine (cytosine arabinoside)), purine analogs and related inhibitors (for example, Mercaptopurine (6-mercaptopurine; 6-MP), Thioguanine (6-thioguanine; TG), and Pentostatin (2′-deoxycoformycin)), vinca alkaloids (for example, Vinblastine (VLB, vinblastine sulfate)) and Vincristine (vincristine sulfate)), epipodophyllotoxins (for example, Etoposide and Teniposide), antibiotics (for example, Dactinomycin (actinomycin D), Daunorubicin (daunomycin; rubidomycin), Doxorubicin, Bleomycin, Plicamycin (mithramycin), and Mitomycin (mitomycin C), enzymes (for example, L-Asparaginase), biological response modifiers (for example, Interferon-alpha and interferon-alpha-2b), platinum coordination compounds (for example, Cisplatin (cis-DDP) and Carboplatin), anthracenedione (Mitoxantrone), substituted ureas (for example, Hydroxyurea), methylhydrazine derivatives (for example, Procarbazine (N-methylhydrazine; MIH), adrenocorticosteroids (for example, Prednisone), progestins (for example, Hydroxyprogesteronie caproate, Medroxyprogesterone, Medroxyprogesterone acetate, and Megestrol acetate), estrogens (for example, Diethylstilbestrol (DES), Diethylstilbestrol diphosphate, Estradiol, and Ethinyl estradiol), antiestrogens (for example, Tamoxifen), androgens (Testosterone proprionate, and Fluoxymesterone), antiandrogens (for example, Flutamide), gonadotropin-releasing horomone analogs (for example, Leuprolide), other hormones and hormone analogs (for example, methyltestosterone, estramustine, estramustine phosphate sodium, chlorotrianisene, and testolactone), and others (for example, dicarbazine, glutamic acid, and mitotane).

In one embodiment, the compositions of the invention are administered in combination with one or more of the following drugs: infliximab (also known as Remicade™ Centocor, Inc.), Trocade (Roche, RO-32-3555), Leflunomide (also known as Arava™ from Hoechst Marion Roussel), Kineret™ (an IL-1 Receptor antagonist also known as Anakinra from Amgen, Inc.)

In a specific embodiment, compositions of the invention are administered in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or combination of one or more of the components of CHOP. In one embodiment, the compositions of the invention are administered in combination with anti-CD20 antibodies, human monoclonal anti-CD20 antibodies. In another embodiment, the compositions of the invention are administered in combination with anti-CD20 antibodies and CHOP, or anti-CD20 antibodies and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. In a specific embodiment, compositions of the invention are administered in combination with Rituximab. In a further embodiment, compositions of the invention are administered with Rituximab and CHOP, or Rituximab and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. In a specific embodiment, compositions of the invention are administered in combination with tositumomab. In a further embodiment, compositions of the invention are administered with tositumomab and CHOP, or tositumomab and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. The anti-CD20 antibodies may optionally be associated with radioisotopes, toxins or cytotoxic prodrugs.

In another specific embodiment, the compositions of the invention are administered in combination Zevalin™. In a further embodiment, compositions of the invention are administered with Zevalin™ and CHOP, or Zevain™ and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. Zevalin™ may be associated with one or more radisotopes. Particularly preferred isotopes are ⁹⁰Y and ¹¹¹In.

In an additional embodiment, the Therapeutics of the invention are administered in combination with cytokines. Cytokines that may be administered with the Therapeutics of the invention include, but are not limited to, IL2, IL3, IL4, IL5, IL6, IL7, IL10, IL12, IL13, IL15, anti-CD40, CD40L, IFN-gamma and TNF-alpha. In another embodiment, Therapeutics of the invention may be administered with any interleukin, including, but not limited to, IL-1alpha, IL-1beta, IL-2, IL-3, IL4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, and IL-21.

In one embodiment, the Therapeutics of the invention are administered in combination with members of the TNF family. TNF, TNF-related or TNF-like molecules that may be administered with the Therapeutics of the invention include, but are not limited to, soluble forms of TNF-alpha, lymphotoxin-alpha (LT-alpha, also known as TNF-beta), LT-beta (found in complex heterotrimer LT-alpha2-beta), OPGL, FasL, CD27L, CD30L, CD40L, 4-1BBL, DcR3, OX40L, TNF-gamma (International Publication No. WO 96/14328), AIM-I (International Publication No. WO 97/33899), endokine-alpha (International Publication No. WO 98/07880), OPG, and neutrokine-alpha (International Publication No. WO 98/18921, OX40, and nerve growth factor (NGF), and soluble forms of Fas, CD30, CD27, CD40 and 4-IBB, TR2 (International Publication No. WO 96/34095), DR3 (International Publication No. WO 97/33904), DR4 (International Publication No. WO 98/32856), TR5 (International Publication No. WO 98/30693), TRANK, TR9 (International Publication No. WO 98/56892), TR10 (International Publication No. WO 98/54202), 312C2 (International Publication No. WO 98/06842), and TR12, and soluble forms CD154, CD70, and CD153.

In an additional embodiment, the Therapeutics of the invention are administered in combination with angiogenic proteins. Angiogenic proteins that may be administered with the Therapeutics of the invention include, but are not limited to, Glioma Derived Growth Factor (GDGF), as disclosed in European Patent Number EP-399816; Platelet Derived Growth Factor-A (PDGF-A), as disclosed in European Patent Number EP-682110; Platelet Derived Growth Factor-B (PDGF-B), as disclosed in European Patent Number EP-282317; Placental Growth Factor (PIGF), as disclosed in International Publication Number WO 92/06194; Placental Growth Factor-2 (PIGF-2), as disclosed in Hauser et al., Growth Factors, 4:259-268 (1993); Vascular Endothelial Growth Factor (VEGF), as disclosed in International Publication Number WO 90/13649; Vascular Endothelial Growth Factor-A (VEGF-A), as disclosed in European Patent Number EP-506477; Vascular Endothelial Growth Factor-2 (VEGF-2), as disclosed in International Publication Number WO 96/39515; Vascular Endothelial Growth Factor B (VEGF-3); Vascular Endothelial Growth Factor B-186 (VEGF-B186), as disclosed in International Publication Number WO 96/26736; Vascular Endothelial Growth Factor-D (VEGF-D), as disclosed in International Publication Number WO 98/02543; Vascular Endothelial Growth Factor-D (VEGF-D), as disclosed in International Publication Number WO 98/07832; and Vascular Endothelial Growth Factor-E (VEGF-E), as disclosed in German Patent Number DE19639601. The above mentioned references are herein incorporated by reference in their entireties.

In an additional embodiment, the Therapeutics of the invention are administered in combination with Fibroblast Growth Factors. Fibroblast Growth Factors that may be administered with the Therapeutics of the invention include, but are not limited to, FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13, FGF-14, and FGF-15.

In an additional embodiment, the Therapeutics of the invention are administered in combination with hematopoietic growth factors. Hematopoietic growth factors that may be administered with the Therapeutics of the invention include, but are not limited to, granulocyte macrophage colony stimulating factor (GM-CSF) (sargramostim, LEUKINE™, PROKINE™), granulocyte colony stimulating factor (G-CSF) (filgrastim, NEUPOGEN™), macrophage colony stimulating factor (M-CSF, CSF-1) erythropoietin (epoetin alfa, EPOGEN™, PROCRRIT™), stem cell factor (SCF, c-kit ligand, steel factor), megakaryocyte colony stimulating factor, PIXY321 (a GMCSF/IL-3 fusion protein), interleulins, especially any one or more of IL-1 through IL-12, interferon-gamma, or thrombopoietin.

In certain embodiments, Therapeutics of the present invention are administered in combination with adrenergic blockers, such as, for example, acebutolol, atenolol, betaxolol, bisoprolol, carteolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol.

In another embodiment, the Therapeutics of the invention are administered in combination with an antiarrhythmic drug (e.g., adenosine, amidoarone, bretylium, digitalis, digoxin, digitoxin, diliazem, disopyramide, esmolol, flecainide, lidocaine, mexiletine, moricizine, phenyloin, procainamide, N-acetyl procainamide, propafenone, propranolol, quinidine, sotalol, tocainide, and verapamil).

In another embodiment, the Therapeutics of the invention are administered in combination with diuretic agents, such as carbonic anhydrase-inhibiting agents (e.g., acetazolamide, dichlorphenamide, and methazolamide), osmotic diuretics (e.g., glycerin, isosorbide, mannitol, and urea), diuretics that inhibit Na⁺—K⁺-2Cl⁻ symport (e.g., furosemide, bumetanide, azosemide, piretanide, tripamide, ethacrynic acid, muzolimine, and torsemide), thiazide and thiazide-like diuretics (e.g., bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichormethiazide, chlorthalidone, indapamide, metolazone, and quinethazone), potassium sparing diuretics (e.g., amiloride and triamterene), and mineralcorticoid receptor antagonists (e.g., spironolactone, canrenone, and potassium canrenoate).

In one embodiment, the Therapeutics of the invention are administered in combination with treatments for endocrine and/or hormone imbalance disorders. Treatments for endocrine and/or hormone imbalance disorders include, but are not limited to, ¹²⁷I, radioactive isotopes of iodine such as ¹³¹I and ¹²³I; recombinant growth hormone, such as HUMATROPE™ (recombinant somatropin); growth hormone analogs such as PROTROPIN™ (somatrem); dopamine agonists such as PARLODEL™ (bromocriptine); somatostatin analogs such as SANDOSTATIN™ (octreotide); gonadotropin preparations such as PREGNYL™, A.P.L.™ and PROFASI™ (chorionic gonadotropin (CG)), PERGONAL™ (menotropins), and METRODIN™ (urofollitropin (uFSH)); synthetic human gonadotropin releasing hormone preparations such as FACRRELT” and LUTREPULSE™ (gonadorelin hydrochloride); synthetic gonadotropin agonists such as LUPRON™ (leuprolide acetate), SUPPRELIN™ (histrelin acetate), SYNAREL™ (nafarelin acetate), and ZOLADEX™ (goserelin acetate); synthetic preparations of thyrotropin-releasing hormone such as RELEFACT TRH™ and THYPINONE™ (protirelin); recombinant human TSH such as THYROGEN™; synthetic preparations of the sodium salts of the natural isomers of thyroid hormones such as L-T₄™, SYNTHROID™ and LEVOTHROID™ (levothyroxine sodium), L-T₃™, CYTOMEL™ and TRIOSTAT™ (liothyroine sodium), and THYROLAR™ (liotrix); antithyroid compounds such as 6-n-propylthiouracil (propylthiouracil), 1-methyl-2-mercaptoimidazole and TAPAZOLE™ (methimazole), NEO-MERCAZOLE™ (carbinazole); beta-adrenergic receptor antagonists such as propranolol and esmolol; Ca²⁺ channel blockers; dexamethasone and iodinated radiological contrast agents such as TELEPAQUE™ (iopanoic acid) and ORAGRAFIN™ (sodium ipodate).

Additional treatments for endocrine and/or hormone imbalance disorders include, but are not limited to, estrogens or congugated estrogens such as ESTRACE™ (estradiol), ESTINYL™ (ethinyl estradiol), PREMARIN™, ESTRATAB™, ORTHO-EST™, OGEN™ and estropipate (estrone), ESTROVIS™ (quinestrol), ESTRADERM™ (estradiol), DELESTROGEN™ and VALERGEN™ (estradiol valerate), DEPO-ESTRADIOL CYPIONATE™ and ESTROJEC™ LA™ (estradiol cypionate); antiestrogens such as NOLVADEX™ (tamoxifen), SEROPHENE™ and CLOMID™ (clomiphene); progestins such as DURALUTIN™ (hydroxyprogesterone caproate), MPA™ and DEPO-PROVERA™ (medroxyprogesterone acetate), PROVERA™ and CYCRIN™ (MPA), MEGACE™ (megestrol acetate), NORLUTIN™ (norethindrone), and NORLUTATE™ and AYGESTIN™ (norethindrone acetate); progesterone implants such as NORPLANT SYSTEM™ (subdermal implants of norgestrel); antiprogestins such as RU 486™ (mifepristone); hormonal contraceptives such as ENOVID™ (norethynodrel plus mestranol), PROGESTASERT™ (intrauterine device that releases progesterone), LOESTRIN™, BREVICON™, MODICON™, GENORA™, NELONA™, NORTNYL™, OVACON-35™ and OVACON-50™ (ethinyl estradiol/norethindrone), LEVLEN™, NORDETTET™, TRI-LEVLEN™ and TRIPHASIL-21™ (ethinyl estradiol/levonorgestrel) LO/OVRAL™ and OVRAL™ (ethinyl estradiol/norgestrel), DEMULEN™ (ethinyl estradiol/ethynodiol diacetate), NORINYL™, ORTHO-NOVUM™, NORETHIN™, GENORA™, and NELOVAT™ (norethindrone/mestranol), DESOGEN™ and ORTHO-CEPT™ (ethinyl estradiol/desogestrel), ORTHO-CYCLEN™ and ORTHO-TRICYCLEN™ (ethinyl estradiol/norgestimate), MICRONOR™ and NOR-QD™ (norethindrone), and OVRETTE™ (norgestrel).

Additional treatments for endocrine and/or hormone imbalance disorders include, but are not limited to, testosterone esters such as rnethenolone acetate and testosterone undecanoate; parenteral and oral androgens such as TESTOJECT-50™ (testosterone), TESTEX™ (testosterone propionate), DEIATESTRYL™ (testosterone enanthate), DEPO-TESTOSTERONE™ (testosterone cypionate), DANOCRINE™ (danazol), HALOTESTIN™ (fluoxymesterone), ORETON METHYL™, TESTRED™ and VIRILON™ (methyltestosterone), and OXANDRIN™ (oxandrolone); testosterone transdermal systems such as TESTODERM™; androgen receptor antagonist and 5-alpha-reductase inhibitors such as ANDROCUR™ (cyproterone acetate), EULEXIN™ (flutamide), and PROSCAR™ (finasteride); adrenocorticotropic hormone preparations such as CORTROSYN™ (cosyntropin); adrenocortical steroids and their synthetic analogs such as ACLOVATE™ (alclometasone dipropionate), CYCLOCORT™ (amcinonide), BECLOVENT™ and VANCERIL™ (beclomethasone dipropionate), CELESTONE™ (betamethasone), BENISONE™ and UTICORT™ (betamethasone benzoate), DIPROSONE™ (betamethasone dipropionate), CELESTONE PHOSPHATE™ (betamethasone sodium phosphate), CELESTONE SOLUSPAN™ (betamethasone sodium phosphate and acetate), BETA-VAL™ and VALISONE™ (betamethasone valerate), TEMOVATE™ (clobetasol propionate), CLODERM™ (clocortolone pivalate), CORTEF™ and HYDROCORTONE™ (cortisol (hydrocortisone)), HYDROCORTONE ACETATE™ (cortisol (hydrocortisone) acetate), LOCOID™ (cortisol (hydrocortisone) butyrate), HYDROCORTONE PHOSPHATE™ (cortisol (hydrocortisone) sodium phosphate), A-HYDROCORT™ and SOLU CORTEF™ (cortisol (hydrocortisone) sodium succinate), WESTCORT™ (cortisol (hydrocortisone) valerate), CORTISONE ACETATE™ (cortisone acetate), DESOWEN™ and TRIDESILON™ (desonide), TOPICORT™ (desoximetasone), DECADRON™ (dexamethasone), DECADRON LA™ (dexamethasone acetate), DECADRON PHOSPHATE™ and HEXADROL PHOSPHATE™ (dexamethasone sodium phosphate), FLORONE™ and MAXIFLOR™ (diflorasone diacetate), FLORINEF ACETATE™ (fludrocortisone acetate), AEROBID™ and NASALIDE™ (flunisolide), FLUONID™ and SYNALAR™ (fluocinolone acetonide), LIDEX™ (fluocinonide), FLUOR-OP™ and FML™ (fluorometholone), CORDRAN™ (flurandrenolide), HALOG™ (halcinonide), HMS LIZUIFILM™ (medrysone), MEDROL™ (methylprednisolone), DEPO-MEDROL™ and MEDROL ACETATE™ (methylprednisone acetate), A-METHAPRED™ and SOLUMEDROL™ (methylprednisolone sodium succinate), ELOCON™ (mometasone furoate), HALDRONE™ (paramethasone acetate), DELTA-CORTEF™ (prednisolone), ECONOPRED™ (prednisolone acetate), HYDELTRASOL™ (prednisolone sodium phosphate), HYDELTRA-T.B.A™ (prednisolone tebutate), DELTASONE™ (prednisone), ARISTOCORT™ and KENACORT™ (triamcinolone), KENALOG™ (triamcinolone acetonide), ARISTOCORT™ and KENACORT DIACETATE™ (triamcinolone diacetate), and ARISTOSPAN™ (triamcinolone hexacetonide); inhibitors of biosynthesis and action of adrenocortical steroids such as CYTADREN™ (aminoglutethimide), NIZORAL™ (ketoconazole), MODRASTANE™ (trilostane), and METOPIRONE™ (metyrapone); bovine, porcine or human insulin or mixtures thereof; insulin analogs; recombinant human insulin such as HUMULN™ and NOVOLIN™; oral hypoglycemic agents such as ORAMDE™ and ORINASE™ (tolbutamide), DIABINESE™ (chlorpropamide), TOLAMIDE™ and TOLINASE™ (tolazamide), DYMELOR™ (acetohexamide), glibenclamide, MICRONASE™, DIBETA™ and GLYNASE™ (glyburide), GLUCOTROL™ (glipizide), and DIAMCRON™ (gliclazide), GLUCOPHAGE™ (metformin), ciglitazone, pioglitazone, and alpha-glucosidase inhibitors; bovine or porcine glucagon; somatostatins such as SANDOSTATIN™ (octreotide); and diazoxides such as PROGLYCEM™ (diazoxide).

In an additional embodiment, the Therapeutics of the invention are administered in combination with drugs effective in treating iron deficiency and hypochromic anemias, including but not limited to, ferrous sulfate (iron sulfate, FEOSOL™), ferrous fumarate (e.g., FEOSTA™), ferrous gluconate (e.g., FERGON™), polysaccharide-iron complex (e.g., NIFEREX™), iron dextran injection (e.g., INFED™), cupric sulfate, pyroxidine, riboflavin, Vitamin B₁₂, cyancobalamin injection (e.g., REDISOL™, RUBRAMIN PC™), hydroxocobalamin, folic acid (e.g., FOLVITE™), leucovorin (folinic acid, 5-CHOH4PteGlu, citrovorum factor) or WELLCOVORIN (Calcium salt of leucovorin), transferrin or ferritin.

In another embodiment, Therapeutics of the invention are administered in combination with vasodilating agents and/or calcium channel blocking agents. Vasodilating agents that may be administered with the Therapeutics of the invention include, but are not limited to, Angiotensin Converting Enzyme (ACE) inhibitors (e.g., papaverine, isoxsuprine, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril, and nylidrin), and nitrates (e.g., isosorbide dinitrate, isosorbide mononitrate, and nitroglycerin). Examples of calcium channel blocking agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil.

In additional embodiments, the Therapeutics of the invention are administered in combination with other therapeutic or prophylactic regimens, such as, for example, radiation therapy.

Example 14 Method of Treating Decreased Levels of the Polypeptide

The present invention relates to a method for treating an individual in need of an increased level of a polypeptide of the invention in the body comprising administering to such an individual a composition comprising a therapeutically effective amount of polypeptides (including agonists thereto), and/or antibodies of the invention. Moreover, it will be appreciated that conditions caused by a decrease in the standard or normal expression level of a polypeptide of the present invention in an individual may be treated by administering agonists of said polypeptide. Thus, the invention also provides a method of treatment of an individual in need of an increased level of the polypeptide comprising administering to such an individual a Therapeutic comprising an amount of the agonist (including polypeptides and antibodies of the present invention) to increase the activity level of the polypeptide in such an individual.

For example, a patient with decreased levels of a polypeptide receives a daily dose 0.1-100 ug/kg of the agonist for six consecutive days. The exact details of the dosing scheme, based on administration and formulation, are provided in Example 13.

Example 15 Method of Treating Increased Levels of the Polypeptide

The present invention also relates to a method of treating an individual in need of a decreased level of a polypeptide of the invention in the body comprising administering to such an individual a composition comprising a therapeutically effective amount of an antagonist of the invention (including polypeptides and antibodies of the invention).

In one example, antisense technology is used to inhibit production of a polypeptide of the present invention. This technology is one example of a method of decreasing levels of a polypeptide, due to a variety of etiologies, such as cancer.

For example, a patient diagnosed with abnormally increased levels of a polypeptide is administered intravenously antisense polynucleotides at 0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment is repeated after a 7-day rest period if the treatment was well tolerated. The antisense polynucleotides of the present invention can be formulated using techniques and formulations described herein (e.g. see Example 13), or otherwise known in the art.

Example 16 Method of Treatment Using Gene Therapy-Ex Vivo

One method of gene therapy transplants fibroblasts, which are capable of expressing a polypeptide, onto a patient. Generally, fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in tissue-culture medium and separated into small pieces. Small chunks of the tissue are placed on a wet surface of a tissue culture flask, approximately ten pieces are placed in each flask. The flask is turned upside down, closed tight and left at room temperature over night. After 24 hours at room temperature, the flask is inverted and the chunks of tissue remain fixed to the bottom of the flask and fresh media (e.g., Ham's F12 media, with 10%. FBS, penicillin and streptomycin) is added. The flasks are then incubated at 37 degree C. for approximately one week.

At this time, fresh media is added and subsequently changed every several days. After an additional two weeks in culture, a monolayer of fibroblasts emerge. The monolayer is trypsinized and scaled into larger flasks.

pMV-7 (Kirschmeier, P. T. et al., DNA, 7:219-25 (1988)), flanked by the long terminal repeats of the Moloney murine sarcoma virus, is digested with EcoRI and HindIII and subsequently treated with calf intestinal phosphatase. The linear vector is fractionated on agarose gel and purified, using glass beads.

The cDNA encoding a polypeptide of the present invention can be amplified using PCR primers which correspond to the 5′ and 3′ end sequences respectively as set forth in Example 1 using primers and having appropriate restriction sites and initiation/stop codons, if necessary. Preferably, the 5′ primer contains an EcoRI site and the 3′ primer includes a HindIII site. Equal quantities of the Moloney murine sarcoma virus linear backbone and the amplified EcoRI and HindIII fragment are added together, in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The ligation mixture is then used to transform bacteria HB101, which are then plated onto agar containing kanamycin for the purpose of confirming that the vector has the gene of interest properly inserted.

The amphotropic pA317 or GP+am12 packaging cells are grown in tissue culture to confluent density in Dulbecco's Modified Eagles Medium (DMEM) with 10% calf serum (CS), penicillin and streptomycin. The MSV vector containing the gene is then added to the media and the packaging cells transduced with the vector. The packaging cells now produce infectious viral particles containing the gene (the packaging cells are now referred to as producer cells).

Fresh media is added to the transduced producer cells, and subsequently, the media is harvested from a 10 cm plate of confluent producer cells. The spent media, containing the infectious viral particles, is filtered through a millipore filter to remove detached producer cells and this media is then used to infect fibroblast cells. Media is removed from a sub-confluent plate of fibroblasts and quickly replaced with the media from the producer cells. This media is removed and replaced with fresh media. If the titer of virus is high, then virtually all fibroblasts will be infected and no selection is required. If the titer is very low, then it is necessary to use a retroviral vector that has a selectable marker, such as neo or his. Once the fibroblasts have been efficiently infected, the fibroblasts are analyzed to determine whether protein is produced.

The engineered fibroblasts are then transplanted onto the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads.

Example 17 Gene Therapy Using Endogenous Genes Corresponding To Polynucleotides of the Invention

Another method of gene therapy according to the present invention involves operably associating the endogenous polynucleotide sequence of the invention with a promoter via homologous recombination as described, for example, in U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication NO: WO 96/29411, published Sep. 26, 1996; International Publication NO: WO 94/12650, published Aug. 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA, 86:8932-8935 (1989); and Zijlstra et al., Nature, 342:435-438 (1989). This method involves the activation of a gene which is present in the target cells, but which is not expressed in the cells, or is expressed at a lower level than desired.

Polynucleotide constructs are made which contain a promoter and targeting sequences, which are homologous to the 5′ non-coding sequence of endogenous polynucleotide sequence, flanking the promoter. The targeting sequence will be sufficiently near the 5′ end of the polynucleotide sequence so the promoter will be operably linked to the endogenous sequence upon homologous recombination. The promoter and the targeting sequences can be amplified using PCR. Preferably, the amplified promoter contains distinct restriction enzyme sites on the 5′ and 3′ ends. Preferably, the 3′ end of the first targeting sequence contains the same restriction enzyme site as the 5′ end of the amplified promoter and the 5′ end of the second targeting sequence contains the same restriction site as the 3′ end of the amplified promoter.

The amplified promoter and the amplified targeting sequences are digested with the appropriate restriction enzymes and subsequently treated with calf intestinal phosphatase. The digested promoter and digested targeting sequences are added together in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The construct is size fractionated on an agarose gel, then purified by phenol extraction and ethanol precipitation.

In this Example, the polynucleotide constructs are administered as naked polynucleotides via electroporation. However, the polynucleotide constructs may also be administered with transfection-facilitating agents, such as liposomes, viral sequences, viral particles, precipitating agents, etc. Such methods of delivery are known in the art.

Once the cells are transfected, homologous recombination will take place which results in the promoter being operably linked to the endogenous polynucleotide sequence. This results in the expression of polynucleotide corresponding to the polynucleotide in the cell. Expression may be detected by immunological staining, or any other method known in the art.

Fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in DMEM+10% fetal calf serum. Exponentially growing or early stationary phase fibroblasts are trypsinized and rinsed from the plastic surface with nutrient medium. An aliquot of the cell suspension is removed for counting, and the remaining cells are subjected to centrifugation. The supernatant is aspirated and the pellet is resuspended in 5 ml of electroporation buffer (20 mM HEPES pH 7.3, 137 mM NaCl, 5 mM KCl, 0.7 mM Na₂ HPO₄, 6 mM dextrose). The cells are recentrifmuged, the supernatant aspirated, and the cells resuspended in electroporation buffer containing 1 mg/ml acetylated bovine serum albumin. The final cell suspension contains approximately 3×10⁶ cells/ml. Electroporation should be performed immediately following resuspension.

Plasmid DNA is prepared according to standard techniques. For example, to construct a plasmid for targeting to the locus corresponding to the polynucleotide of the invention, plasmid pUC18 (MBI Fermentas, Amherst, N.Y.) is digested with HindIII. The CMV promoter is amplified by PCR with an XbaI site on the 5′ end and a BamHI site on the 3′ end. Two non-coding sequences are amplified via PCR: one non-coding sequence (fragment 1) is amplified with a HindIII site at the 5′ end and an Xba site at the 3′end; the other non-coding sequence (fragment 2) is amplified with a BamHI site at the 5′end and a HindIII site at the 3′end. The CMV promoter and the fragments (1 and 2) are digested with the appropriate enzymes (CMV promoter—XbaI and BamI; fragment 1—XbaI; fragment 2—BamHI) and ligated together. The resulting ligation product is digested with HindIII, and ligated with the HindIII-digested pUC18 plasmid.

Plasmid DNA is added to a sterile cuvette with a 0.4 cm electrode gap (Bio-Rad). The final DNA concentration is generally at least 120 μg/ml. 0.5 ml of the cell suspension (containing approximately 1.5.×10⁶ cells) is then added to the cuvette, and the cell suspension and DNA solutions are gently mixed. Electroporation is performed with a Gene-Pulser apparatus (Bio-Rad). Capacitance and voltage are set at 960 μF and 250-300 V, respectively. As voltage increases, cell survival decreases, but the percentage of surviving cells that stably incorporate the introduced DNA into their genome increases dramatically. Given these parameters, a pulse time of approximately 14-20 mSec should be observed.

Electroporated cells are maintained at room temperature for approximately 5 min, and the contents of the cuvette are then gently removed with a sterile transfer pipette. The cells are added directly to 10 ml of prewarmed nutrient media (DMEM with 15% calf serum) in a 10 cm dish and incubated at 37 degree C. The following day, the media is aspirated and replaced with 10 ml of fresh media and incubated for a further 16-24 hours.

The engineered fibroblasts are then injected into the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads. The fibroblasts now produce the protein product. The fibroblasts can then be introduced into a patient as described above.

Example 18 Method of Treatment Using Gene Therapy—In Vivo

Another aspect of the present invention is using in vivo gene therapy methods to prevent, treat, and/or ameliorate hematopoietic and hematologic diseases and disorders. The gene therapy method relates to the introduction of naked nucleic acid (DNA, RNA, and antisense DNA or RNA) sequences into an animal to increase or decrease the expression of the polypeptide. The polynucleotide of the present invention may be operatively linked to (i.e., associated with) a promoter or any other genetic elements necessary for the expression of the polypeptide by the target tissue. Such gene therapy and delivery techniques and methods are known in the art, see, for example, WO90/11092, WO98/11779; U.S. Pat. Nos. 5,693,622, 5,705,151, 5,580,859; Tabata et al., Cardiovasc. Res. 35(3):470-479 (1997); Chao et al., Pharmacol. Res. 35(6):517-522 (1997); Wolff, Neuromuscul. Disord. 7(5):314-318 (1997); Schwartz et al., Gene Ther. 3(5):405-411 (1996); Tsurumi et al., Circulation 94(12):3281-3290 (1996) (incorporated herein by reference).

The polynucleotide constructs may be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, intestine and the like). The polynucleotide constructs can be delivered in a pharmaceutically acceptable liquid or aqueous carrier.

The term “naked” polynucleotide, DNA or RNA, refers to sequences that are free from any delivery vehicle that acts to assist, promote, or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. However, the polynucleotides of the present invention may also be delivered in liposome formulations (such as those taught in Felgner P. L. et al. (1995) Ann. NY Acad. Sci. 772:126-139 and Abdallah B. et al. (1995) Biol. Cell 85(1):1-7) which can be prepared by methods well known to those skilled in the art.

The polynucleotide vector constructs used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Any strong promoter known to those skilled in the art can be used for driving the expression of DNA. Unlike other gene therapy techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.

The polynucleotide construct can be delivered to the interstitial space of tissues within an animal, including muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.

For the naked polynucleotide injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 g/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration. The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose. In addition, naked polynucleotide constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.

The dose response effects of injected polynucleotide in muscle in vivo is determined as follows. Suitable template DNA for production of mRNA coding for polypeptide of the present invention is prepared in accordance with a standard recombinant DNA methodology. The template DNA, which may be either circular or linear, is either used as naked DNA or complexed with liposomes. The quadriceps muscles of mice are then injected with various amounts of the template DNA.

Five to six week old female and male Balb/C mice are anesthetized by intraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision is made on the anterior thigh, and the quadriceps muscle is directly visualized. The template DNA is injected in 0.1 ml of carrier in a 1 cc syringe through a 27 gauge needle over one minute, approximately 0.5 cm from the distal insertion site of the muscle into the knee and about 0.2 cm deep: A suture is placed over the injection site for future localization, and the skin is closed with stainless steel clips.

After an appropriate incubation time (e.g., 7 days) muscle extracts are prepared by excising the entire quadriceps. Every fifth 15 um cross-section of the individual quadriceps muscles is histochemically stained for protein expression. A time course for protein expression may be done in a similar fashion except that quadriceps from different mice are harvested at different times. Persistence of DNA in muscle following injection may be determined by Southern blot analysis after preparing total cellular DNA and HIRT supernatants from injected and control mice. The results of the above experimentation in mice can be used to extrapolate proper dosages and other treatment parameters in humans and other animals using naked DNA.

Example 19 Transgenic Animals

The polypeptides of the invention can also be expressed in transgenic animals. Animals of any species, including, but not limited to, mice, rats, rabbits, hamsters, guinea pigs, pigs, micro-pigs, goats, sheep, cows and non-human primates, e.g., baboons, monkeys, and chimpanzees may be used to generate transgenic animals. In a specific embodiment, techniques described herein or otherwise known in the art, are used to express polypeptides of the invention in humans, as part of a gene therapy protocol.

Any technique known in the art may be used to introduce the transgene (i.e., polynucleotides of the invention) into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection (Paterson et al., Appl. Microbiol. Biotechnol. 40:691-698 (1994); Carver et al., Biotechnology (NY) 11:1263-1270 (1993); Wright et al., Biotechnology (NY) 9:830-834 (1991); and Hoppe et al., U.S. Pat. No. 4,873,191 (1989)); retrovirus mediated gene transfer into germ lines (Van der Putten et al., Proc. Natl. Acad. Sci., USA 82:6148-6152 (1985)), blastocysts or embryos; gene targeting in embryonic stem cells (Thompson et al., Cell 56:313-321 (1989)); electroporation of cells or embryos (Lo, 1983, Mol Cell. Biol. 3:1803-1814 (1983)); introduction of the polynucleotides of the invention using a gene gun (see, e.g., Ulmer et al., Science 259:1745 (1993); introducing nucleic acid constructs into embryonic pleuripotent stem cells and transferring the stem cells back into the blastocyst; and sperm-mediated gene transfer (Lavitrano et al., Cell 57:717-723 (1989); etc. For a review of such techniques, see Gordon, “Transgenic Animals,” Intl. Rev. Cytol. 115:171-229 (1989), which is incorporated by reference herein in its entirety.

Any technique known in the art may be used to produce transgenic clones containing polynucleotides of the invention, for example, nuclear transfer into enucleated oocytes of nuclei from cultured embryonic, fetal, or adult cells induced to quiescence (Campell et al., Nature 380:64-66 (1996); Wilmut et al., Nature 385:810-813 (1997)).

The present invention provides for transgenic animals that carry the transgene in all their cells, as well as animals which carry the transgene in some, but not all their cells, Le., mosaic animals or chimeric. The transgene may be integrated as a single transgene or as multiple copies such as in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, for example, the teaching of Lasko et al. (Lasko et al., Proc. Natl. Acad. Sci. USA 89:6232-6236 (1992)). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art. When it is desired that the polynucleotide transgene be integrated into the chromosomal site of the endogenous gene, gene targeting is preferred. Briefly, when such a technique is to be utilized, vectors containing some nucleotide sequences homologous to the endogenous gene are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous gene. The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous gene in only that cell type, by following, for example, the teaching of Gu et al. (Gu et al., Science 265:103-106 (1994)). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

Once transgenic animals have been generated, the expression of the recombinant gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (rt-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.

Once the founder animals are produced, they may be bred, inbred, outbred, or crossbred to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: outbreeding of founder animals with more than one integration site in order to establish separate lines; inbreeding of separate lines in order to produce compound transgenics that express the transgene at higher levels because of the effects of additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site in order to both augment expression and eliminate the need for screening of animals by DNA analysis; crossing of separate homozygous lines to produce compound heterozygous or homozygous lines; and breeding to place the transgene on a distinct background that is appropriate for an experimental model of interest.

Transgenic animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

Example 20 Knock-Out Animals

Endogenous gene expression can also be reduced by inactivating or “knocking out” the gene and/or its promoter using targeted homologous recombination. (e.g., see Smithies et al., Nature 317:230-234 (1985); Thomas & Capecchi, Cell 51:503-512 (1987); Thompson et al., Cell 5:313-321 (1989); each of which is incorporated by reference herein in its entirety). For example, a mutant, non-functional polynucleotide of the invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous polynucleotide sequence (either the coding regions or regulatory regions of the gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express polypeptides of the invention in vivo. In another embodiment, techniques known in the art are used to generate knockouts in cells that contain, but do not express the gene of interest. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the targeted gene. Such approaches are particularly suited in research and agricultural fields where modifications to embryonic stem cells can be used to generate animal offspring with an inactive targeted gene (e.g., see Thomas & Capecchi 1987 and Thompson 1989, supra). However this approach can be routinely adapted for use in humans provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors that will be apparent to those of skill in the art.

In further embodiments of the invention, cells that are genetically engineered to express the polypeptides of the invention, or alternatively, that are genetically engineered not to express the polypeptides of the invention (e.g., knockouts) are administered to a patient in vivo. Such cells may be obtained from the patient (i.e., animal, including human) or an MHC compatible donor and can include, but are not limited to fibroblasts, bone marrow cells, blood cells (e.g., lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cells are genetically engineered in vitro using recombinant DNA techniques to introduce the coding sequence of polypeptides of the invention into the cells, or alternatively, to disrupt the coding sequence and/or endogenous regulatory sequence associated with the polypeptides of the invention, e.g., by transduction (using viral vectors, and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including, but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc. The coding sequence of the polypeptides of the invention can be placed under the control of a strong constitutive or inducible promoter or promoter/enhancer to achieve expression, and preferably secretion, of the polypeptides of the invention. The engineered cells which express and preferably secrete the polypeptides of the invention can be introduced into the patient systemically, e.g., in the circulation, or intraperitoneally.

Alternatively, the cells can be incorporated into a matrix and implanted in the body, e.g., genetically engineered fibroblasts can be implanted as part of a skin graft; genetically engineered endothelial cells can be implanted as part of a lymphatic or vascular graft. (See, for example, Anderson et al. U.S. Pat. No. 5,399,349; and Mulligan & Wilson, U.S. Pat. No. 5,460,959 each of which is incorporated by reference herein in its entirety).

When the cells to be administered are non-autologous or non-MHC compatible cells, they can be administered using well known techniques which prevent the development of a host immune response against the introduced cells. For example, the cells may be introduced in an encapsulated form which, while allowing for an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the host immune system.

Transgenic and “knock-out” animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

Example 21 Assays Detecting Stimulation or Inhibition of B cell Proliferation and Differentiation

Generation of functional humoral immune responses requires both soluble and cognate signaling between B-lineage cells and their microenvironment. Signals may impart a positive stimulus that allows a B-lineage cell to continue its programmed development, or a negative stimulus that instructs the cell to arrest its current developmental pathway. To date, numerous stimulatory and inhibitory signals have been found to influence B cell responsiveness including IL-2, IL4, IL-5, IL6, IL-7, IL10, IL-13, IL-14 and IL-15. Interestingly, these signals are by themselves weak effectors but can, in combination with various co-stimulatory proteins, induce activation, proliferation, differentiation, homing, tolerance and death among B cell populations.

One of the best studied classes of B-cell co-stimulatory proteins is the TNF-superfamily. Within this family CD40, CD27, and CD30 along with their respective ligands CD154, CD70, and CD153 have been found to regulate a variety of immune responses. Assays which allow for the detection and/or observation of the proliferation and differentiation of these B-cell populations and their precursors are valuable tools in determining the effects various proteins may have on these B-cell populations in terms of proliferation and differentiation. Listed below are two assays designed to allow for the detection of the differentiation, proliferation, or inhibition of B-cell populations and their precursors.

In Vitro Assay-Agonists or antagonists of the invention can be assessed for its ability to induce activation, proliferation, differentiation or inhibition and/or death in B-cell populations and their precursors. The activity of the agonists or antagonists of the invention on purified human tonsillar B cells, measured qualitatively over the dose range from 0.1 to 10,000 ng/mL, is assessed in a standard B-lymphocyte co-stimulation assay in which purified tonsillar B cells are cultured in the presence of either formalin-fixed Staphylococcus aureus Cowan I (SAC) or immobilized anti-human IgM antibody as the priming agent. Second signals such as IL-2 and IL-15 synergize with SAC and IgM crosslinking to elicit B cell proliferation as measured by tritiated-thymidine incorporation. Novel synergizing agents can be readily identified using this assay. The assay involves isolating human tonsillar B cells by magnetic bead (MACS) depletion of CD3-positive cells. The resulting cell population is greater than 95% B cells as assessed by expression of CD45R(B220).

Various dilutions of each sample are placed into individual wells of a 96-well plate to which are added 10⁵ B-cells suspended in culture medium (RPMI 1640 containing 10% FBS, 5×10⁻⁵M 2ME, 100 U/ml penicillin, 10 ug/ml streptomycin, and 10⁻⁵ dilution of SAC) in a total volume of 150 ul. Proliferation or inhibition is quantitated by a 20 h pulse (1 uCi/well) with 3H-thymidine (6.7 Ci/mM) beginning 72 h post factor addition. The positive and negative controls are IL2 and medium respectively.

In vivo Assay-BALB/c mice are injected (i.p.) twice per day with buffer only, or 2 mg/Kg of agonists or antagonists of the invention, or truncated forms thereof. Mice receive this treatment for 4 consecutive days, at which time they are sacrificed and various tissues and serum collected for analyses. Comparison of H&E sections from normal spleens and spleens treated with agonists or antagonists of the invention identify the results of the activity of the agonists or antagonists on spleen cells, such as the diffusion of peri-arterial lymphatic sheaths, and/or significant increases in the nucleated cellularity of the red pulp regions, which may indicate the activation of the differentiation and proliferation of B-cell populations. Immunohistochemical studies using a B cell marker, anti-CD45R(B220), are used to determine whether any physiological changes to splenic cells, such as splenic disorganization, are due to increased B-cell representation within loosely defined B-cell zones that infiltrate established T-cell regions.

Flow cytometric analyses of the spleens from mice treated with agonist or antagonist is used to indicate whether the agonists or antagonists specifically increases the proportion of ThB+, CD45R(B220) dull B cells over that which is observed in control mice.

Likewise, a predicted consequence of increased mature B-cell representation in vivo is a relative increase in serum Ig titers. Accordingly, serum IgM and IgA levels are compared between buffer and agonists or antagonists-treated mice.

The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 22 T Cell Proliferation Assay

A CD3-induced proliferation assay is performed on PBMCs and is measured by the uptake of ³H-thymidine. The assay is performed as follows. Ninety-six well plates are coated with 100 μl/well of mAb to CD3 (HIT3a, Pharmingen) or isotype-matched control mAb (B33.1) overnight at 4 degrees C. (1 μg/ml in 0.05M bicarbonate buffer, pH 9.5), then washed three times with PBS. PBMC are isolated by F/H gradient centrifugation from human peripheral blood and added to quadruplicate wells (5×10⁴/well) of mAb coated plates in RPMI containing 10% FCS and P/S in the presence of varying concentrations of agonists or antagonists of the invention (total volume 200 ul). Relevant protein buffer and medium alone are controls. After 48 hr. culture at 37 degrees C., plates are spun for 2 min. at 1000 rpm and 100 μl of supernatant is removed and stored −20 degrees C. for measurement of IL-2 (or other cytokines) if effect on proliferation is observed. Wells are supplemented with 100 ul of medium containing 0.5 uCi of ³H-thymidine and cultured at 37 degrees C. for 18-24 hr. Wells are harvested and incorporation of ³H-thymidine used as a measure of proliferation. Anti-CD3 alone is the positive control for proliferation. IL-2 (100 U/ml) is also used as a control which enhances proliferation. Control antibody which does not induce proliferation of T cells is used as the negative control for the effects of agonists or antagonists of the invention.

The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 23 Effect of Agonists or Antagonists of the Invention on the Expression of MHC Class II, Costimulatory and Adhesion Molecules and Cell Differentiation of Monocytes and Monocyte-Derived Human Dendrite Cells

Dendritic cells are generated by the expansion of proliferating precursors found in the peripheral blood: adherent PBMC or elutriated monocytic fractions are cultured for 7-10 days with GM-CSF (50 ng/ml) and IL4 (20 ng/ml). These dendritic cells have the characteristic phenotype of immature cells (expression of CD1, CD80, CD86, CD40 and MHC class 11 antigens). Treatment with activating factors, such as TNf-α, causes a rapid change in surface phenotype (increased expression of MHC class I and II, costimulatory and adhesion molecules, downregulation of FCγRII, upregulation of CD83). These changes correlate with increased antigen-presenting capacity and with functional maturation of the dendritic cells.

FACS analysis of surface antigens is performed as follows. Cells are treated 1-3 days with increasing concentrations of agonist or antagonist of the invention or LPS (positive control), washed with PBS containing 1% BSA and 0.02 mM sodium azide, and then incubated with 1:20 dilution of appropriate FFIC- or PE-labeled monoclonal antibodies for 30 minutes at 4 degrees C. After an additional wash, the labeled cells are analyzed by flow cytometry on a FACScan (Becton Dickinson).

Effect on the production of cytokines. Cytokines generated by dendritic cells, in particular IL-12, are important in the initiation of T-cell dependent immune responses. IL-12 strongly influences the development of Thl helper T-cell immune response, and induces cytotoxic T and NK cell function. An ELISA is used to measure the IL-12 release as follows. Dendritic cells (10⁶/ml) are treated with increasing concentrations of agonists or antagonists of the invention for 24 hours. LPS (100 ng/ml) is added to the cell culture as positive control. Supernatants from the cell cultures are then collected and analyzed for IL-12 content using commercial ELISA kit (e.g., R & D Systems (Minneapolis, Minn.)). The standard protocols provided with the kits are used.

Effect on the expression of MHC Class II costimulatory and adhesion molecules. Three major families of cell surface antigens can be identified on monocytes: adhesion molecules, molecules involved in antigen presentation, and Fc receptor. Modulation of the expression of MHC class II antigens and other costimulatory molecules, such as B7 and ICAM-1, may result in changes in the antigen presenting capacity of monocytes and ability to induce T cell activation. Increased expression of Fc receptors may correlate with improved monocyte cytotoxic activity, cytokine release and phagocytosis.

FACS analysis is used to examine the surface antigens as follows. Monocytes are treated 1-5 days with increasing concentrations of agonists or antagonists of the invention or LPS (positive control), washed with PBS containing 1% BSA and 0.02 mM sodium azide, and then incubated with 1:20 dilution of appropriate FITC- or PE-labeled monoclonal antibodies for 30 minutes at 4 degrees C. After an additional wash, the labeled cells are analyzed by flow cytometry on a FACScan (Becton Dickinson).

Monocyte activation and/or increased survival. Assays for molecules that activate (or alternatively, inactivate) monocytes and/or increase monocyte survival (or alternatively, decrease monocyte survival) are known in the art and may routinely be applied to determine whether a molecule of the invention functions as an inhibitor or activator of monocytes. Agonists or antagonists of the invention can be screened using the three assays described below. For each of these assays, Peripheral blood mononuclear cells (PBMC) are purified from single donor leukopacks (American Red Cross, Baltimore, Md.) by centrifugation through a Histopaque gradient (Sigma). Monocytes are isolated from PBMC by counterflow centrifugal elutriation.

Monocyte Survival Assay. Human peripheral blood monocytes progressively lose viability when cultured in absence of serum or other stimuli. Their death results from internally regulated processes (apoptosis). Addition to the culture of activating factors, such as TNF-alpha dramatically improves cell survival and prevents DNA fragmentation. Propidium iodide (PI) staining is used to measure apoptosis as follows. Monocytes are cultured for 48 hours in polypropylene tubes in serum-free medium (positive control), in the presence of 100 ng/ml TNF-alpha (negative control), and in the presence of varying concentrations of the compound to be tested. Cells are suspended at a concentration of 2×10⁶/ml in PBS containing PI at a final concentration of 5 μg/ml, and then incubated at room temperature for 5 minutes before FACScan analysis. PI uptake has been demonstrated to correlate with DNA fragmentation in this experimental paradigm.

Effect on cytokine release. An important function of monocytes/macrophages is their regulatory activity on other cellular populations of the immune system through the release of cytokines after stimulation. An ELISA to measure cytokine release is performed as follows. Human monocytes are incubated at a density of 5×10⁵ cells/ml with increasing concentrations of agonists or antagonists of the invention and under the same conditions, but in the absence of agonists or antagonists. For IL-12 production, the cells are primed overnight with IFN (100 U/ml) in the presence of agonist or antagonist of the invention. LPS (10 ng/ml) is then added. Conditioned media are collected after 24 h and kept frozen until use. Measurement of TNF-alpha, IL-10, MCP-1 and IL-8 is then performed using a commercially available ELISA kit (e.g., R & D Systems (Minneapolis, Minn.)) and applying the standard protocols provided with the kit.

Oxidative burst. Purified monocytes are plated in 96-w plate at 2-1×10 ⁵ cell/well. Increasing concentrations of agonists or antagonists of the invention are added to the wells in a total volume of 0.2 ml culture medium (RPMI 1640+10% FCS, glutamine and antibiotics). After 3 days incubation, the plates are centrifuged and the medium is removed from the wells. To the macrophage monolayers, 0.2 ml per well of phenol red solution (140 mM NaCl, 10 mM potassium phosphate buffer pH 7.0, 5.5 mM dextrose, 0.56 mM phenol red and 19 U/ml of HRPO) is added, together with the stimulant (200 nM PMA). The plates are incubated at 37° C. for 2 hours and the reaction is stopped by adding 20 μl 1N NaOH per well. The absorbance is read at 610 nm. To calculate the amount of H₂O₂ produced by the macrophages, a standard curve of a H₂O₂ solution of known molarity is performed for each experiment.

The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 24 Diabetic Mouse and Glucocorticoid-Impaired Wound Healing Models

Diabetic db+/db+Mouse Model.

To demonstrate that an agonist or antagonist of the invention accelerates the healing process, the genetically diabetic mouse model of wound healing is used. The full thickness wound healing model in the db+/db+ mouse is a well characterized, clinically relevant and reproducible model of impaired wound healing. Healing of the diabetic wound is dependent on formation of granulation tissue and re-epithelialization rather than contraction (Gartner, M. H. et al., J. Surg. Res. 52:389 (1992); Greenhalgh, D. G. et al., Am. J. Pathol. 136:1235 (1990)).

The diabetic animals have many of the characteristic features observed in Type II diabetes mellitus. Homozygous (db+/db+) mice are obese in comparison to their normal heterozygous (db+/+m) littermates. Mutant diabetic (db+/db+) mice have a single autosomal recessive mutation on chromosome 4 (db+) (Coleman et al. Proc. Natl. Acad. Sci. USA 77:283-293 (1982)). Animals show polyphagia, polydipsia and polyuria. Mutant diabetic mice (db+/db+) have elevated blood glucose, increased or normal insulin levels, and suppressed cell-mediated immunity (Mandel et al, J. Immunol. 120:1375 (1978); Debray-Sachs, M. et al., Clin. Exp. Immunol. 51(1):1-7 (1983); Leiter et al., Am. J. of Pathol. 114:46-55 (1985)). Peripheral neuropathy, myocardial complications, and microvascular lesions, basement membrane thickening and glomerular filtration abnormalities have been described in these animals (Norido, F. et al., Exp. Neurol. 83(2):221-232 (1984); Robertson et al, Diabetes 29(1):60-67 (1980); Giacomelli et al, Lab Invest. 40(4):460-473 (1979); Coleman, D. L., Diabetes 31 (Suppl):1-6 (1982)). These homozygous diabetic mice develop hyperglycemia that is resistant to insulin analogous to human type II diabetes (Mandel et al., J. Immunol. 120:1375-1377 (1978)).

The characteristics observed in these animals suggests that healing in this model may be similar to the healing observed in human diabetes (Greenhalgh, et al., Am. J. of Pathol. 136:1235-1246 (1990)).

Genetically diabetic female C57BL/KsJ (db+/db+) mice and their non-diabetic (db+/+m) heterozygous littermates are used in this study (Jackson Laboratories). The animals are purchased at 6 weeks of age and are 8 weeks old at the beginning of the study. Animals are individually housed and received food and water ad libitum. All manipulations are performed using aseptic techniques. The experiments are conducted according to the rules and guidelines of Human Genome Sciences, Inc. Institutional Animal Care and Use Committee and the Guidelines for the Care and Use of Laboratory Animals.

Wounding protocol is performed according to previously reported methods (Tsuboi, R. and Rifkin, D. B., J. Exp. Med. 172:245-251 (1990)). Briefly, on the day of wounding, animals are anesthetized with an intraperitoneal injection of Avertin (0.01 mg/mL), 2,2,2-tribromoethanol and 2-methyl-2-butanol dissolved in deionized water. The dorsal region of the animal is shaved and the skin washed with 70% ethanol solution and iodine. The surgical area is dried with sterile gauze prior to wounding. An 8 mm full-thickness wound is then created using a Keyes tissue punch. Immediately following wounding, the surrounding skin is gently stretched to eliminate wound expansion. The wounds are left open for the duration of the experiment. Application of the treatment is given topically for 5 consecutive days commencing on the day of wounding. Prior to treatment, wounds are gently cleansed with sterile saline and gauze sponges.

Wounds are visually examined and photographed at a fixed distance at the day of surgery and at two day intervals thereafter. Wound closure is determined by daily measurement on days 1-5 and on day 8. Wounds are measured horizontally and vertically using a calibrated Jameson caliper. Wounds are considered healed if granulation tissue is no longer visible and the wound is covered by a continuous epithelium.

An agonist or antagonist of the invention is administered using at a range different doses, from 4 mg to 500 mg per wound per day for 8 days in vehicle. Vehicle control groups received 50 mL of vehicle solution.

Animals are euthanized on day 8 with an intraperitoneal injection of sodium pentobarbital (300 mg/kg). The wounds and surrounding skin are then harvested for histology and immunohistochemistry. Tissue specimens are placed in 10% neutral buffered formalin in tissue cassettes between biopsy sponges for further processing.

Three groups of 10 animals each (5 diabetic and 5 non-diabetic controls) are evaluated: 1) Vehicle placebo control, 2) untreated group, and 3) treated group.

Wound closure is analyzed by measuring the area in the vertical and horizontal axis and obtaining the total square area of the wound. Contraction is then estimated by establishing the differences between the initial wound area (day 0) and that of post treatment (day 8). The wound area on day 1 is 64 mm², the corresponding size of the dermal punch. Calculations are made using the following formula: [Open area on day 8]−[Open area on day 1]/[Open area on day 1]

Specimens are fixed in 10% buffered formalin and paraffin embedded blocks are sectioned perpendicular to the wound surface (5 mm) and cut using a Reichert-Jung microtome. Routine hematoxylin-eosin (H&E) staining is performed on cross-sections of bisected wounds. Histologic examination of the wounds are used to assess whether the healing process and the morphologic appearance of the repaired skin is altered by treatment with an agonist or antagonist of the invention. This assessment included verification of the presence of cell accumulation, inflammatory cells, capillaries, fibroblasts, re-epithelialization and epidermal maturity (Greenhalgh, D. G. et al., Am. J. Pathol. 136:1235 (1990)). A calibrated lens micrometer is used by a blinded observer.

Tissue sections are also stained immunohistochemically with a polyclonal rabbit anti-human keratin antibody using ABC Elite detection system. Human skin is used as a positive tissue control while non-immune IgG is used as a negative control. Keratinocyte growth is determined by evaluating the extent of reepithelialization of the wound using a calibrated lens micrometer.

Proliferating cell nuclear antigen/cyclin (PCNA) in skin specimens is demonstrated by using anti-PCNA antibody (1:50) with an ABC Elite detection system. Human colon cancer served as a positive tissue control and human brain tissue is used as a negative tissue control. Each specimen included a section with omission of the primary antibody and substitution with non-immune mouse IgG. Ranking of these sections is based on the extent of proliferation on a scale of 0-8, the lower side of the scale reflecting slight proliferation to the higher side reflecting intense proliferation.

Experimental data are analyzed using an unpaired t test. A p value of <0.05 is considered significant.

Steroid Impaired Rat Model

The inhibition of wound healing by steroids has been well documented in various in vitro and in vivo systems (Wahl, Glucocorticoids and Wound healing. In: Anti-Inflammatory Steroid Action: Basic and Clinical Aspects. 280-302 (1989); Wahl et al., J. Immunol. 115: 476-481 (1975); Werb et al., J. Exp. Med. 147:1684-1694 (1978)). Glucocorticoids retard wound healing by inhibiting angiogenesis, decreasing vascular permeability (Ebert et al., An. Intern. Med. 37:701-705 (1952)), fibroblast proliferation, and collagen synthesis (Beck et al., Growth Factors. 5: 295-304 (1991); Haynes et al., J. Clin. Invest. 61: 703-797 (1978)) and producing a transient reduction of circulating monocytes (Haynes et al., J. Clin. Invest. 61: 703-797 (1978); Wahl, “Glucocorticoids and wound healing”, In: Antiinflammatory Steroid Action: Basic and Clinical Aspects, Academic Press, New York, pp. 280-302 (1989)). The systemic administration of steroids to impaired wound healing is a well establish phenomenon in rats (Beck et al., Growth Factors. 5: 295-304 (1991); Haynes et al., J. Clin. Invest. 61: 703-797 (1978); Wahl, “Glucocorticoids and wound healing”, In: Antiinflammatory Steroid Action: Basic and Clinical Aspects, Academic Press, New York, pp. 280-302 (1989); Pierce et al., Proc. Natl. Acad. Sci. USA 86: 2229-2233 (1989)).

To demonstrate that an agonist or antagonist of the invention can accelerate the healing process, the effects of multiple topical applications of the agonist or antagonist on full thickness excisional skin wounds in rats in which healing has been impaired by the systemic administration of methylprednisolone is assessed.

Young adult male Sprague Dawley rats weighing 250-300 g (Charles River Laboratories) are used in this example. The animals are purchased at 8 weeks of age and are 9 weeks old at the beginning of the study. The healing response of rats is impaired by the systemic administration of methylprednisolone (17 mg/kg/rat intramuscularly) at the time of wounding. Animals are individually housed and received food and water ad libitum. All manipulations are performed using aseptic techniques. This study is conducted according to the rules and guidelines of Human Genome Sciences, Inc. Institutional Animal Care and Use Committee and the Guidelines for the Care and Use of Laboratory Animals.

The wounding protocol is followed according to section A, above. On the day of wounding, animals are anesthetized with an intramuscular injection of ketamine (50 mg/kg) and xylazine (5 mg/kg). The dorsal region of the animal is shaved and the skin washed with 70% ethanol and iodine solutions. The surgical area is dried with sterile gauze prior to wounding. An 8 mm full-thickness wound is created using a Keyes tissue punch. The wounds are left open for the duration of the experiment. Applications of the testing materials are given topically once a day for 7 consecutive days commencing on the day of wounding and subsequent to methylprednisolone administration. Prior to treatment, wounds are gently cleansed with sterile saline and gauze sponges.

Wounds are visually examined and photographed at a fixed distance at the day of wounding and at the end of treatment. Wound closure is determined by daily measurement on days 1-5 and on day 8. Wounds are measured horizontally and vertically using a calibrated Jameson caliper. Wounds are considered healed if granulation tissue is no longer visible and the wound is covered by a continuous epithelium.

The agonist or antagonist of the invention is administered using at a range different doses, from 4 mg to 500 mg per wound per day for 8 days in vehicle. Vehicle control groups received 50 mL of vehicle solution.

Animals are euthanized on day 8 with an intraperitoneal injection of sodium pentobarbital (300 mg/kg). The wounds and surrounding skin are then harvested for histology. Tissue specimens are placed in 10% neutral buffered formalin in tissue cassettes between biopsy sponges for further processing.

Three groups of 10 animals each (5 with methylprednisolone and 5 without glucocorticoid) are evaluated: 1) Untreated group 2) Vehicle placebo control 3) treated groups.

Wound closure is analyzed by measuring the area in the vertical and horizontal axis and obtaining the total area of the wound. Closure is then estimated by establishing the differences between the initial wound area (day 0) and that of post treatment (day 8). The wound area on day 1 is 64 mm², the corresponding size of the dermal punch. Calculations are made using the following formula: [Open area on day 8]−[Open area on day 1]/[Open area on day 1]

Specimens are fixed in 10% buffered formalin and paraffin embedded blocks are sectioned perpendicular to the wound surface (5 mm) and cut using an Olympus microtome. Routine hematoxylin-eosin (H&E) staining is performed on cross-sections of bisected wounds. Histologic examination of the wounds allows assessment of whether the healing process and the morphologic appearance of the repaired skin is improved by treatment with an agonist or antagonist of the invention. A calibrated lens micrometer is used by a blinded observer to determine the distance of the wound gap.

Experimental data are analyzed using an unpaired t test. A p value of <0.05 is considered significant.

The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 25 Lymphadema Animal Model

The purpose of this experimental approach is to create an appropriate and consistent lymphedema model for testing the therapeutic effects of an agonist or antagonist of the invention in lymphangiogenesis and reestablishment of the lymphatic circulatory system in the rat hind limb. Effectiveness is measured by swelling volume of the affected limb, quantification of the amount of lymphatic vasculature, total blood plasma protein, and histopathology. Acute lymphedema is observed for 7-10 days. Perhaps more importantly, the chronic progress of the edema is followed for up to 34 weeks.

Prior to beginning surgery, blood sample is drawn for protein concentration analysis. Male rats weighing approximately ˜350 g are dosed with Pentobarbital. Subsequently, the right legs are shaved from knee to hip. The shaved area is swabbed with gauze soaked in 70% EtOH. Blood is drawn for serum total protein testing. Circumference and volumetric measurements are made prior to injecting dye into paws after marking 2 measurement levels (0.5 cm above heel, at mid-pt of dorsal paw). The intradermal dorsum of both right and left paws are injected with 0.05 ml of 1% Evan's Blue. Circumference and volumetric measurements are then made following injection of dye into paws.

Using the knee joint as a landmark, a mid-leg inguinal incision is made circumferentially allowing the femoral vessels to be located. Forceps and hemostats are used to dissect and separate the skin flaps. After locating the femoral vessels, the lymphatic vessel that runs along side and underneath the vessel(s) is located. The main lymphatic vessels in this area are then electrically coagulated or suture ligated.

Using a microscope, muscles in back of the leg (near the semitendinosis and adductors) are bluntly dissected. The popliteal lymph node is then located. The 2 proximal and 2 distal lymphatic vessels and distal blood supply of the popliteal node are then ligated by suturing. The popliteal lymph node, and any accompanying adipose tissue, is then removed by cutting connective tissues.

Care is taken to control any mild bleeding resulting from this procedure. After lymphatics are occluded, the skin flaps are sealed by using liquid skin (Vetbond) (AJ Buck). The separated skin edges are sealed to the underlying muscle tissue while leaving a gap of ˜0.5 cm around the leg. Skin also may be anchored by suturing to underlying muscle when necessary.

To avoid infection, animals are housed individually with mesh (no bedding). Recovering animals are checked daily through the optimal edematous peak, which typically occurred by day 5-7. The plateau edematous peak are then observed. To evaluate the intensity of the lymphedema, the circumference and volumes of 2 designated places on each paw before operation and daily for 7 days are measured. The effect of plasma proteins on lymphedema is determined and whether protein analysis is a useful testing perimeter is also investigated. The weights of both control and edematous limbs are evaluated at 2 places. Analysis is performed in a blind manner.

Circumference Measurements: Under brief gas anesthetic to prevent limb movement, a cloth tape is used to measure limb circumference. Measurements are done at the ankle bone and dorsal paw by 2 different people and those 2 readings are averaged. Readings are taken from both control and edematous limbs.

Volumetric Measurements: On the day of surgery, animals are anesthetized with Pentobarbital and are tested prior to surgery. For daily volumetrics animals are under brief halothane anesthetic (rapid immobilization and quick recovery), and both legs are shaved and equally marked using waterproof marker on legs. Legs are first dipped in water, then dipped into instrument to each marked level then measured by Buxco edema software (Chen/Victor). Data is recorded by one person, while the other is dipping the limb to marked area.

Blood-plasma protein measurements: Blood is drawn, spun, and serum separated prior to surgery and then at conclusion for total protein and Ca2⁺ comparison.

Limb Weight Comparison: After drawing blood, the animal is prepared for tissue collection. The limbs are amputated using a quillitine, then both experimental and control legs are cut at the ligature and weighed. A second weighing is done as the tibio-cacaneal joint is disarticulated and the foot is weighed.

Histological Preparations: The transverse muscle located behind the knee (popliteal) area is dissected and arranged in a metal mold, filled with freezeGel, dipped into cold methylbutane, placed into labeled sample bags at −80 EC until sectioning. Upon sectioning, the muscle is observed under fluorescent microscopy for lymphatics.

The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 26 Suppression of TNF Alpha-Induced Adhesion Molecule Expression by an Agonist or Antagonist of the Invention

The recruitment of lymphocytes to areas of inflammation and angiogenesis involves specific receptor-ligand interactions between cell surface adhesion molecules (CAMs) on lymphocytes and the vascular endothelium. The adhesion process, in both normal and pathological settings, follows a multi-step cascade that involves intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) expression on endothelial cells (EC). The expression of these molecules and others on the vascular endothelium determines the efficiency with which leukocytes may adhere to the local vasculature and extravasate into the local tissue during the development of an inflammatory response. The local concentration of cytokines and growth factor participate in the modulation of the expression of these CAMs.

Tumor necrosis factor alpha (TNF-a), a potent proinflammatory cytokine, is a stimulator of all three CAMs on endothelial cells and may be involved in a wide variety of inflammatory responses, often resulting in a pathological outcome.

The potential of an agonist or antagonist of the invention to mediate a suppression of TNF-a induced CAM expression can be examined. A modified ELISA assay which uses ECs as a solid phase absorbent is employed to measure the amount of CAM expression on TNF-a treated ECs when co-stimulated with a member of the FGF family of proteins.

To perform the experiment, human umbilical vein endothelial cell (HUVEC) cultures are obtained from pooled cord harvests and maintained in growth medium (EGM-2; Clonetics, San Diego, Calif.) supplemented with 10% FCS and 1% penicillin/streptomycin in a 37 degree C. humidified incubator containing 5% CO₂. HUVECs are seeded in 96-well plates at concentrations of 1×10⁴ cells/well in EGM medium at 37 degree C. for 18-24 hrs or until confluent. The monolayers are subsequently washed 3 times with a serum-free solution of RPMI-1640 supplemented with 100 U/ml penicillin and 100 mg/ml streptomycin, and treated with a given cytokine and/or growth factor(s) for 24 h at 37 degree C. Following incubation, the cells are then evaluated for CAM expression.

Human Umbilical Vein Endothelial cells (HUVECs) are grown in a standard 96 well plate to confluence. Growth medium is removed from the cells and replaced with 90 ul of 199 Medium (10% FBS). Samples for testing and positive or negative controls are added to the plate in triplicate (in 10 ul volumes). Plates are incubated at 37 degree C. for either 5 h (selectin and integrin expression) or 24 h (integrin expression only). Plates are aspirated to remove medium and 100 μl of 0.1% paraformaldehyde-PBS (with Ca++ and Mg++) is added to each well. Plates are held at 4° C. for 30 min.

Fixative is then removed from the wells and wells are washed 1× with PBS(+Ca, Mg)+0.5% BSA and drained. Do not allow the wells to dry. Add 10 μl of diluted primary antibody to the test and control wells. Anti-ICAM-1-Biotin, Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at a concentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stock antibody). Cells are incubated at 37° C. for 30 min. in a humidified environment. Wells are washed X3 with PBS(+Ca, Mg)+0.5% BSA.

Then add 20 μl of diluted ExtrAvidin-Alkaline Phosphotase (1:5,000 dilution) to each well and incubated at 37° C. for 30 min. Wells are washed X3 with PBS(+Ca, Mg)+0.5% BSA. 1 tablet of p-Nitrophenol Phosphate pNPP is dissolved in 5 ml of glycine buffer (pH 10.4). 100 μl of pNPP substrate in glycine buffer is added to each test well. Standard wells in triplicate are prepared from the working dilution of the ExtrAvidin-Alkaline Phosphotase in glycine buffer: 1:5,000 (10⁰)>10^(−0.5)>10⁻¹>10^(−1.5). 5 μl of each dilution is added to triplicate wells and the resulting AP content in each well is 5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent must then be added to each of the standard wells. The plate must be incubated at 37° C. for 4 h. A volume of 50 μl of 3M NaOH is added to all wells. The results are quantified on a plate reader at 405 nm. The background subtraction option is used on blank wells filled with glycine buffer only. The template is set up to indicate the concentration of AP-conjugate in each standard well [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated as amount of bound AP-conjugate in each sample.

The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 27 Production of Polypeptide of the Invention for High-Throughput Screening Assays

The following protocol produces a supernatant containing polypeptide of the present invention to be tested. This supernatant can then be used in the Screening Assays described in Examples 29-37.

First, dilute Poly-D-Lysine (644 587 Boehringer-Mannheim) stock solution (1 mg/ml in PBS) 1:20 in PBS (w/o calcium or magnesium 17-516F Biowhittaker) for a working solution of 50 ug/ml. Add 200 ul of this solution to each well (24 well plates) and incubate at RT for 20 minutes. Be sure to distribute the solution over each well (note: a 12-channel pipetter may be used with tips on every other channel). Aspirate off the Poly-D-Lysine solution and rinse with 1 ml PBS (Phosphate Buffered Saline). The PBS should remain in the well until just prior to plating the cells and plates may be poly-lysine coated in advance for up to two weeks.

Plate 293T cells (do not carry cells past P+20) at 2×10⁵ cells/well in 0.5 ml DMEM (Dulbecco's Modified Eagle Medium)(with 4.5 G/L glucose and L-glutamine (12-604F Biowhittaker))/10% heat inactivated FBS(14-503F Biowhittaker)/1× Penstrep(17-602E Biowhittaker). Let the cells grow overnight.

The next day, mix together in a sterile solution basin: 300 ul Lipofectamine (18324-012 Gibco/BRL) and 5 ml Optimem I (31985070 Gibco/BRL)/96-well plate. With a small volume multi-channel pipetter, aliquot approximately 2 ug of an expression vector containing a polynucleotide insert, produced by the methods described in Examples 8-10, into an appropriately labeled 96-well round bottom plate. With a multi-channel pipetter, add 50 ul of the Lipofectamine/Optimem I mixture to each well. Pipette up and down gently to mix. Incubate at RT 15-45 minutes. After about 20 minutes, use a multi-channel pipetter to add 150 ul Optimem I to each well. As a control, one plate of vector DNA lacking an insert should be transfected with each set of transfections.

Preferably, the transfection should be performed by tag-teaming the following tasks. By tag-teaming, hands on time is cut in half, and the cells do not spend too much time on PBS. First, person A aspirates off the media from four 24-well plates of cells, and then person B rinses each well with 0.5-1 ml PBS. Person A then aspirates off PBS rinse, and person B, using a 12-channel pipetter with tips on every other channel, adds the 200 ul of DNA/Lipofectamine/Optimem I complex to the odd wells first, then to the even wells, to each row on the 24-well plates. Incubate at 37 degree C. for 6 hours.

While cells are incubating, prepare appropriate media, either 1% BSA in DMEM with 1× penstrep, or HGS CHO-5 media (116.6 mg/L of CaCl₂ (anhyd); 0.00130 mg/L CuSO₄-5H₂O; 0.050 mg/L of Fe(NO₃)₃-9H₂O; 0.417 mg/L of FeSO₄.7H₂O; 311.80 mg/L of Kcl; 28.64 mg/L of MgCl₂; 48.84 mg/L of MgSO₄; 6995.50 mg/L of NaCl; 2400.0 mg/L of NaHCO₃; 62.50 mg/L of NaH₂PO₄—H₂O; 71.02 mg/L of Na₂HPO4; 0.4320 mg/L of ZnSO₄.7H20; 0.002 mg/L of Arachidonic Acid; 1.022 mg/L of Cholesterol; 0.070 mg/L of DL-alpha-Tocopherol-Acetate; 0.0520 mg/mL of Linoleic Acid; 0.010 mg/L of Linolenic Acid; 0.010 mg/L of Myristic Acid; 0.010 mg/L of Oleic Acid; 0.010 mg/L of Palmitric Acid; 0.010 mg/L of Palmitic Acid; 100 mg/L of Pluronic F-68; 0.010 mg/L of Stearic Acid; 2.20 mg/L of Tween 80; 4551 mg/L of D-Glucose; 130.85 mg/ml of L-Alanine; 147.50 mg/ml of L-Arginine-HCL; 7.50 mg/ml of L-Asparagine-H₂O; 6.65 mg/ml of L-Aspartic Acid; 29.56 mg/ml of L-Cystine-2HCL-H₂O; 31.29 mg/ml of L-Cystine-2HCL; 7.35 mg/ml of L-Glutamic Acid; 365.0 mg/ml of L-Glutamine; 18.75 mg/ml of Glycine; 52.48 mg/ml of L-Histidine-HCL-H₂O; 106.97 mg/ml of L-Isoleucine; 111.45 mg/ml of L-Leucine; 163.75 mg/ml of L-Lysine HCL; 32.34 mg/ml of L-Methionine; 68.48 mg/ml of L-Phenylalainine; 40.0 mg/ml of L-Proline; 26.25 mg/ml of L-Serine; 101.05 mg/ml of L-Threonine; 19.22 mg/ml of L-Tryptophan; 91.79 mg/ml of L-Tryrosine-2Na-2H₂O; and 99.65 mg/ml of L-Valine; 0.0035 mg/L of Biotin; 3.24 mg/L of D-Ca Pantothenate; 11.78 mg/L of Choline Chloride; 4.65 mg/L of Folic Acid; 15.60 mg/L of i-Inositol; 3.02 mg/L of Niacinamide; 3.00 mg/L of Pyridoxal HCL; 0.031 mg/L of Pyridoxine HCL; 0.319 mg/L of Riboflavin; 3.17 mg/L of Thiamine HCL; 0.365 mg/L of Thymidine; 0.680 mg/L of Vitamin B12; 25 mM of HEPES Buffer; 2.39 mg/L of Na Hypoxanthine; 0.105 mg/L of Lipoic Acid; 0.081 mg/L of Sodium Putrescine-2HCL; 55.0 mg/L of Sodium Pyruvate; 0.0067 mg/L of Sodium Selenite; 20 uM of Ethanolamine; 0.122 mg/L of Ferric Citrate; 41.70 mg/L of Methyl-B-Cyclodextrin complexed with Linoleic Acid; 33.33 mg/L of Methyl-B-Cyclodextrin complexed with Oleic Acid; 10 mg/L of Methyl-B-Cyclodextrin complexed with Retinal Acetate. Adjust osmolarity to 327 mOsm) with 2 mm glutamine and 1× penstrep. (BSA (81-068-3 Bayer) 100 gm dissolved in 1L DMEM for a 10% BSA stock solution). Filter the media and collect 50 ul for endotoxin assay in 15 ml polystyrene conical.

The transfection reaction is terminated, preferably by tag-teaming, at the end of the incubation period. Person A aspirates off the transfection media, while person B adds 1.5 ml appropriate media to each well. Incubate at 37 degree C. for 45 or 72 hours depending on the media used: 1% BSA for 45 hours or CHO-5 for 72 hours.

On day four, using a 300 ul multichannel pipetter, aliquot 600 ul in one 1 ml deep well plate and the remaining supernatant into a 2 ml deep well. The supernatants from each well can then be used in the assays described in Examples 29-35.

It is specifically understood that when activity is obtained in any of the assays described below using a supernatant, the activity originates from either the polypeptide of the present invention directly (e.g., as a secreted protein) or by polypeptide of the present invention inducing expression of other proteins, which are then secreted into the supernatant. Thus, the invention further provides a method of identifying the protein in the supernatant characterized by an activity in a particular assay.

Example 28 Construction of GAS Reporter Construct

One signal transduction pathway involved in the differentiation and proliferation of cells is called the Jaks-STATs pathway. Activated proteins in the Jaks-STATs pathway bind to gamma activation site “GAS” elements or interferon-sensitive responsive element (“ISRE”), located in the promoter of many genes. The binding of a protein to these elements alter the expression of the associated gene.

GAS and ISRE elements are recognized by a class of transcription factors called Signal Transducers and Activators of Transcription, or “STATs.” There are six members of the STATs family. Stat1 and Stat3 are present in many cell types, as is Stat2 (as response to IFN-alpha is widespread). Stat4 is more restricted and is not in many cell types though it has been found in T helper class I, cells after treatment with IL-12. Stat5 was originally called mammary growth factor, but has been found at higher concentrations in other cells including myeloid cells. It can be activated in tissue culture cells by many cytokines.

The STATs are activated to translocate from the cytoplasm to the nucleus upon tyrosine phosphorylation by a set of kinases known as the Janus Kinase (“Jaks”) family. Jaks represent a distinct family of soluble tyrosine kinases and include Tyk2, Jak1, Jak2, and Jak3. These kinases display significant sequence similarity and are generally catalytically inactive in resting cells.

The Jaks are activated by a wide range of receptors summarized in the Table below. (Adapted from review by Schidler and Darnell, Ann. Rev. Biochem. 64:621-51 (1995)). A cytokine receptor family, capable of activating Jaks, is divided into two groups: (a) Class 1 includes receptors for IL-2, IL-3, L4, IL-6, IL-7, IL-9, IL-11, IL-12, IL-15, Epo, PRL, GH, G-CSF, GM-CSF, LIF, CNTF, and thrombopoietin; and (b) Class 2 includes IFN-a, IFN-g, and IL-10. The Class 1 receptors share a conserved cysteine motif (a set of four conserved cysteines and one tryptophan) and a WSXWS motif (a membrane proximal region encoding Trp-Ser-Xaa-Trp-Ser (SEQ ID NO: 2)).

Thus, on binding of a ligand to a receptor, Jaks are activated, which in turn activate STATs, which then translocate and bind to GAS elements. This entire process is encompassed in the Jaks-STATs signal transduction pathway. Therefore, activation of the Jaks-STATs pathway, reflected by the binding of the GAS or the ISRE element, can be used to indicate proteins involved in the proliferation and differentiation of cells. For example, growth factors and cytokines are known to activate the Jaks-STATs pathway (See Table below). Thus, by using GAS elements linked to reporter molecules, activators of the Jaks-STATs pathway can be identified. JAKs Ligand tyk2 Jak1 Jak2 Jak3 STATS GAS (elements) or ISRE IFN family IFN-a/B + + − − 1, 2, 3 ISRE IFN-g + + − 1 GAS (IRF1 > Lys6 > IFP) Il-10 + ? ? − 1, 3 gp130 family IL-6 (Pleiotropic) + + + ? 1, 3 GAS (IRF1 > Lys6 > IFP) Il-11 (Pleiotropic) ? + ? ? 1, 3 OnM (Pleiotropic) ? + + ? 1, 3 LIF (Pleiotropic) ? + + ? 1, 3 CNTF (Pleiotropic) −/+ + + ? 1, 3 G-CSF (Pleiotropic) ? + ? ? 1, 3 IL-12 (Pleiotropic) + − + + 1, 3 g-C family IL-2 (lymphocytes) − + − + 1, 3, 5 GAS IL-4 (lymph/myeloid) − + − + 6 GAS (IRF1 = IFP >> Ly6)(IgH) IL-7 (lymphocytes) − + − + 5 GAS IL-9 (lymphocytes) − + − + 5 GAS IL-13 (lymphocyte) − + ? ? 6 GAS IL-15 ? + ? + 5 GAS gp140 family IL-3 (myeloid) − − + − 5 GAS (IRF1 > IFP >> Ly6) IL-5 (myeloid) − − + − 5 GAS GM-CSF (myeloid) − − + − 5 GAS Growth hormone family GH ? − + − 5 PRL ? +/− + − 1, 3, 5 EPO ? − + − 5 GAS(B- CAS > IRF1 = IFP >> Ly6) Receptor Tyrosine Kinases EGF ? + + − 1, 3 GAS (IRF1) PDGF ? + + − 1, 3 CSF-1 ? + + − 1, 3 GAS (not IRF1)

To construct a synthetic GAS containing promoter element, which is used in the Biological Assays described in Examples 29-30, a PCR based strategy is employed to generate a GAS-SV40 promoter sequence. The 5′ primer contains four tandem copies of the GAS binding site found in the IRF1 promoter and previously demonstrated to bind STATs upon induction with a range of cytolines (Rothman et al., Immunity 1:457-468 (1994).), although other GAS or ISRE elements can be used instead. The 5′ primer also contains 18 bp of sequence complementary to the SV40 early promoter sequence and is flanked with an XhoI site. The sequence of the 5′ primer is: 5′:GCGCCTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCGAA (SEQ ID NO: 3) ATGATTTCCCCGAAATATCTGCCATCTCAATTAG:3′

The downstream primer is complementary to the SV40 promoter and is flanked with a Hind III site: 5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′ (SEQ ID NO: 4)

PCR amplification is performed using the SV40 promoter template present in the B-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI/Hind III and subcloned into BLSK2-. (Stratagene.) Sequencing with forward and reverse primers confirms that the insert contains the following sequence: 5′:CTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCGAAATGA (SEQ ID NO: 5) TTTCCCCGAAATATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCC GCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAA TTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAG TGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTT:3′

With this GAS promoter element linked to the SV40 promoter, a GAS:SEAP2 reporter construct is next engineered. Here, the reporter molecule is a secreted alkaline phosphatase, or “SEAP.” Clearly, however, any reporter molecule can be instead of SEAP, in this or in any of the other Examples. Well known reporter molecules that can be used instead of SEAP include chloramphenicol acetyltransferase (CAT), luciferase, alkaline phosphatase, B-galactosidase, green fluorescent protein (GFP), or any protein detectable by an antibody.

The above sequence confirmed synthetic GAS-SV40 promoter element is subcloned into the pSEAP-Promoter vector obtained from Clontech using HindIII and XhoI, effectively replacing the SV40 promoter with the amplified GAS:SV40 promoter element, to create the GAS-SEAP vector. However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.

Thus, in order to generate mammalian stable cell lines expressing the GAS-SEAP reporter, the GAS-SEAP cassette is removed from the GAS-SEAP vector using SalI and NotI, and inserted into a backbone vector containing the neomycin resistance gene, such as pGFP-1 (Clontech), using these restriction sites in the multiple cloning site, to create the GAS-SEAP/Neo vector. Once this vector is transfected into mammalian cells, this vector can then be used as a reporter molecule for GAS binding as described in Examples 29-30.

Other constructs can be made using the above description and replacing GAS with a different promoter sequence. For example, construction of reporter molecules containing EGR and NF-KB promoter sequences are described in Example 31. However, many other promoters can be substituted using the protocols described in these Examples. For instance, SRE, IL-2, NFAT, or Osteocalcin promoters can be substituted, alone or in combination (e.g., GAS/NF-KB/EGR, GASNF-KB, II-2/NFAT, or NF-KB/GAS). Similarly, other cell lines can be used to test reporter construct activity, such as HELA (epithelial), HUVEC (endothelial), Reh (B-cell), Saos-2 (osteoblast), HUVAC (aortic), or Cardiomyocyte.

Example 29 High-Throughput Screening Assay for T-Cell Activity

The following protocol is used to assess T-cell activity by identifying factors, and determining whether supernate containing a polypeptide of the invention proliferates and/or differentiates T-cells. T-cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 28. Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS signal transduction pathway. The T-cell used in this assay is Jurkat T-cells (ATCC Accession No. TIB-152), although Molt-3 cells (ATCC Accession No. CRL-1552) and Molt-4 cells (ATCC Accession No. CRL-1582) cells can also be used.

Jurkat T-cells are lymphoblastic CD4+ Th1 helper cells. In order to generate stable cell lines, approximately 2 million Jurkat cells are transfected with the GAS-SEAP/neo vector using DMRIE-C (Life Technologies)(transfection procedure described below). The transfected cells are seeded to a density of approximately 20,000 cells per well and transfectants resistant to 1 mg/ml genticin selected. Resistant colonies are expanded and then tested for their response to increasing concentrations of interferon gamma. The dose response of a selected clone is demonstrated.

Specifically, the following protocol will yield sufficient cells for 75 wells containing 200 ul of cells. Thus, it is either scaled up, or performed in multiple to generate sufficient cells for multiple 96 well plates. Jurkat cells are maintained in RPMI+10% serum with 1% Pen-Strep. Combine 2.5 mils of OPTI-MEM (Life Technologies) with 10 ug of plasmid DNA in a T25 flask. Add 2.5 ml OPTI-MEM containing 50 ul of DMRIE-C and incubate at room temperature for 1545 mins.

During the incubation period, count cell concentration, spin down the required number of cells (10⁷ per transfection), and resuspend in OPTI-MEM to a final concentration of 10⁷ cells/ml. Then add 1 ml of 1×10⁷ cells in OPTI-MEM to T25 flask and incubate at 37 degree C. for 6 hrs. After the incubation, add 10 ml of RPMI+15% serum.

The Jurkat:GAS-SEAP stable reporter lines are maintained in RPMI+10% serum, 1 mg/ml Genticin, and 1% Pen-Strep. These cells are treated with supernatants containing polypeptide of the present invention or polypeptide of the present invention induced polypeptides as produced by the protocol described in Example 27.

On the day of treatment with the supernatant, the cells should be washed and resuspended in fresh RPMI+10% serum to a density of 500,000 cells per ml. The exact number of cells required will depend on the number of supernatants being screened. For one 96 well plate, approximately 10 million cells (for 10 plates, 100 million cells) are required.

Transfer the cells to a triangular reservoir boat, in order to dispense the cells into a 96 well dish, using a 12 channel pipette. Using a 12 channel pipette, transfer 200 ul of cells into each well (therefore adding 100,000 cells per well).

After all the plates have been seeded, 50 ul of the supernatants are transferred directly from the 96 well plate containing the supernatants into each well using a 12 channel pipette. In addition, a dose of exogenous interferon gamma (0.1, 1.0, 10 ng) is added to wells H9, H10, and H11 to serve as additional positive controls for the assay.

The 96 well dishes containing Jurkat cells treated with supernatants are placed in an incubator for 48 hrs (note: this time is variable between 48-72 hrs). 35 ul samples from each well are then transferred to an opaque 96 well plate using a 12 channel pipette. The opaque plates should be covered (using sellophene covers) and stored at −20 degree C. until SEAP assays are performed according to Example 32. The plates containing the remaining treated cells are placed at 4 degree C. and serve as a source of material for repeating the assay on a specific well if desired.

As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate Jurkat T cells. Over 30 fold induction is typically observed in the positive control wells.

The above protocol may be used in the generation of both transient, as well as, stable transfected cells, which would be apparent to those of skill in the art.

Example 30 High-Throughput Screening Assay Identifying Myeloid Activity

The following protocol is used to assess myeloid activity of polypeptide of the present invention by determining whether polypeptide of the present invention proliferates and/or differentiates myeloid cells. Myeloid cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 28. Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS signal transduction pathway. The myeloid cell used in this assay is U937, a pre-monocyte cell line, although TF-1, HL60, or KG1 can be used.

To transiently transfect U937 cells with the GAS/SEAP/Neo construct produced in Example 28, a DEAE-Dextran method (Kharbanda et. al., 1994, Cell Growth & Differentiation, 5:259-265) is used. First, harvest 2×10⁷ U937 cells and wash with PBS. The U937 cells are usually grown in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/ml penicillin and 100 mg/ml streptomycin.

Next, suspend the cells in 1 ml of 20 mM Tris-HCl (pH 7.4) buffer containing 0.5 mg/ml DEAE-Dextran, 8 ug GAS-SEAP2 plasmid DNA, 140 mM NaCl, 5 mM KCl, 375 uM Na₂HPO₄.7H₂O, 1 mM MgCl2, and 675 uM CaCl₂. Incubate at 37 degrees C. for 45 min.

Wash the cells with RPMI 1640 medium containing 10% FBS and then resuspend in 10 ml complete medium and incubate at 37 degree C. for 36 hr.

The GAS-SEAP/U937 stable cells are obtained by growing the cells in 400 ug/ml G418. The G418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 400 ug/ml G418 for couple of passages.

These cells are tested by harvesting 1×10⁸ cells (this is enough for ten 96-well plates assay) and wash with PBS. Suspend the cells in 200 ml above described growth medium, with a final density of 5×10⁵ cells/ml. Plate 200 ul cells per well in the 96-well plate (or 1×10⁵ cells/well).

Add 50 ul of the supernatant prepared by the protocol described in Example 27. Incubate at 37 degee C for 48 to 72 hr. As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate U937 cells. Over 30 fold induction is typically observed in the positive control wells. SEAP assay the supernatant according to the protocol described in Example 32.

Example 31 High-Throughput Screening Assay for T-cell Activity

NF-KB (Nuclear Factor KB) is a transcription factor activated by a wide variety of agents including the inflammatory cytokines IL-1 and TNF, CD30 and CD40, lymphotoxin-alpha and lymphotoxin-beta, by exposure to LPS or thrombin, and by expression of certain viral gene products. As a transcription factor, NF-KB regulates the expression of genes involved in immune cell activation, control of apoptosis (NF-KB appears to shield cells from apoptosis), B and T-cell development, anti-viral and antimicrobial responses, and multiple stress responses.

In non-stimulated conditions, NF-KB is retained in the cytoplasm with I-KB (Inhibitor KB). However, upon stimulation, I-KB is phosphorylated and degraded, causing NP-KB to shuttle to the nucleus, thereby activating transcription of target genes. Target genes activated by NF-KB include IL-2, IL6, GM-CSF, ICAM-1 and class 1 MHC.

Due to its central role and ability to respond to a range of stimuli, reporter constructs utilizing the NF-KB promoter element are used to screen the supernatants produced in Example 27. Activators or inhibitors of NF-KB would be useful in detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating diseases. For example, inhibitors of NF-KB could be used to treat those diseases related to the acute or chronic activation of NF-KB, such as rheumatoid arthritis.

To construct a vector containing the NF-KB promoter element, a PCR based strategy is employed. The upstream primer contains four tandem copies of the NF-KB binding site (GGGGACTTTCCC) (SEQ ID NO: 8), 18 bp of sequence complementary to the 5′ end of the SV40 early promoter sequence, and is flanked with an XhoI site: 5′:GCGGCCTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGACTTT (SEQ ID NO: 9) CCATCCTGCCATCTCAATTAG:3′

The downstream primer is complementary to the 3′ end of the SV40 promoter and is flanked with a Hind III site: 5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′ (SEQ ID NO: 4)

PCR amplification is performed using the SV40 promoter template present in the pB-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI and Hind III and subcloned into BLSK2-. (Stratagene) Sequencing with the T7 and T3 primers confirms the insert contains the following sequence: 5′:CTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGACTTTCCATC (SEQ ID NO: 10) TGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCT AACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATTTATG CAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTT TGGAGGCCTAGGCTTTTGCAAAAAGCTT:3′

Next, replace the SV40 minimal promoter element present in the pSEAP2-promoter plasmid (Clontech) with this NF-KB/SV40 fragment using XhoI and HindIII. However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.

In order to generate stable mammalian cell lines, the NF-KB/SV40/SEAP cassette is removed from the above NF-KB/SEAP vector using restriction enzymes SalI and NotI, and inserted into a vector containing neomycin resistance. Particularly, the NF-KB/SV40/SEAP cassette was inserted into pGFP-1 (Clontech), replacing the GFP gene, after restricting pGFP-1 with SalI and NotI.

Once NF-KB/SV40/SEAP/Neo vector is created, stable Jurkat T-cells are created and maintained according to the protocol described in Example 29. Similarly, the method for assaying supernatants with these stable Jurkat T-cells is also described in Example 29. As a positive control, exogenous TNF alpha (0.1, 1, 10 ng) is added to wells H9, H10, and H11, with a 5-10 fold activation typically observed.

Example 32 Assay for SEAP Activity

As a reporter molecule for the assays described in Examples 29-31, SEAP activity is assayed using the Tropix Phospho-light Kit (Cat BP-400) according to the following general procedure. The Tropix Phospho-light Kit supplies the Dilution, Assay, and Reaction Buffers used below.

Prime a dispenser with the 2.5× Dilution Buffer and dispense 15 ul of 2.5× dilution buffer into Optiplates containing 35 ul of a supernatant. Seal the plates with a plastic sealer and incubate at 65 degree C for 30 min. Separate the Optiplates to avoid uneven heating.

Cool the samples to room temperature for 15 minutes. Empty the dispenser and prime with the Assay Buffer. Add 50 ml Assay Buffer and incubate at room temperature 5 min. Empty the dispenser and prime with the Reaction Buffer (see the Table below). Add 50 ul Reaction Buffer and incubate at room temperature for 20 minutes. Since the intensity of the chemiluminescent signal is time dependent, and it takes about 10 minutes to read 5 plates on a luminometer, thus one should treat 5 plates at each time and start the second set 10 minutes later.

Read the relative light unit in the luminometer. Set H12 as blank, and print the results. An increase in chemiluminescence indicates reporter activity. Reaction Buffer Formulation: # of plates Rxn buffer diluent (ml) CSPD (ml) 10 60 3 11 65 3.25 12 70 3.5 13 75 3.75 14 80 4 15 85 4.25 16 90 4.5 17 95 4.75 18 100 5 19 105 5.25 20 110 5.5 21 115 5.75 22 120 6 23 125 6.25 24 130 6.5 25 135 6.75 26 140 7 27 145 7.25 28 150 7.5 29 155 7.75 30 160 8 31 165 8.25 32 170 8.5 33 175 8.75 34 180 9 35 185 9.25 36 190 9.5 37 195 9.75 38 200 10 39 205 10.25 40 210 10.5 41 215 10.75 42 220 11 43 225 11.25 44 230 11.5 45 235 11.75 46 240 12 47 245 12.25 48 250 12.5 49 255 12.75 50 260 13

Example 33 High-Throughput Screening Assay Identifying Changes in Small Molecule Concentration and Membrane Permeability

Binding of a ligand to a receptor is known to alter intracellular levels of small molecules, such as calcium, potassium, sodium, and pH, as well as alter membrane potential. These alternations can be measured in an assay to identify supernatants which bind to receptors of a particular cell. Although the following protocol describes an assay for calcium, this protocol can easily be modified to detect changes in potassium, sodium, pH, membrane potential, or any other small molecule which is detectable by a fluorescent probe.

The following assay uses Fluorometric Imaging Plate Reader (“FLIPR”) to measure changes in fluorescent molecules (Molecular Probes) that bind small molecules. Clearly, any fluorescent molecule detecting a small molecule can be used instead of the calcium fluorescent molecule, fluo-4 (Molecular Probes, Inc.; catalog no. F-14202), used here.

For adherent cells, seed the cells at 10,000 cells/well in a Co-star black 96-well plate with clear bottom. The plate is incubated in a CO₂ incubator for 20 hours. The adherent cells are washed two times in Biotek washer with 200 ul of HBSS (Hank's Balanced Salt Solution) leaving 100 ul of buffer after the final wash.

A stock solution of 1 mg/ml fluo-4 is made in 10% pluronic acid DMSO. To load the cells with fluo-4, 50 ul of 12 ug/ml fluo-4 is added to each well. The plate is incubated at 37 degrees C in a CO₂ incubator for 60 min. The plate is washed four times in the Biotek washer with HBSS leaving 100 ul of buffer.

For non-adherent cells, the cells are spun down from culture media. Cells are resuspended to 2-5=10⁶ cells/ml with HBSS in a 50-ml conical tube. 4 ul of 1 mg/ml fluo-4 solution in 10% pluronic acid DMSO is added to each ml of cell suspension. The tube is then placed in a 37 degrees C. water bath for 30-60 min. The cells are washed twice with HBSS, resuspended to 1×10⁶ cells/ml, and dispensed into a microplate, 100 ul/well. The plate is centrifuged at 1000 rpm for 5 min. The plate is then washed once in Denley Cell Wash with 200 ul, followed by an aspiration step to 100 ul final volume.

For a non-cell based assay, each well contains a fluorescent molecule, such as fluo-4. The supernatant is added to the well, and a change in fluorescence is detected.

To measure the fluorescence of intracellular calcium, the FLIPR is set for the following parameters: (1) System gain is 300-800 mW; (2) Exposure time is 0.4 second; (3) Camera F/stop is F/2; (4) Excitation is 488 nm; (5) Emission is 530 nm; and (6) Sample addition is 50 ul. Increased emission at 530 nm indicates an extracellular signaling event caused by the a molecule, either polypeptide of the present invention or a molecule induced by polypeptide of the present invention, which has resulted in an increase in the intracellular Ca⁺⁺ concentration.

Example 34 High-Throughput Screening Assay Identifying Tyrosine Kinase Activity

The Protein Tyrosine Kinases (PTK) represent a diverse group of transmembrane and cytoplasmic kinases. Within the Receptor Protein Tyrosine Kinase RPTK) group are receptors for a range of mitogenic and metabolic growth factors including the PDGF, FGF, EGF, NGF, HGF and Insulin receptor subfamilies. In addition there are a large family of RPTKs for which the corresponding ligand is unknown. Ligands for RPTKs include mainly secreted small proteins, but also membrane-bound and extracellular matrix proteins.

Activation of RPTK by ligands involves ligand-mediated receptor dimerization, resulting in transphosphorylation of the receptor subunits and activation of the cytoplasmic tyrosine kinases. The cytoplasmic tyrosine kinases include receptor associated tyrosine kinases of the src-family (e.g., src, yes, Ick, lyn, fyn) and non-receptor linked and cytosolic protein tyrosine kinases, such as the Jak family, members of which mediate signal transduction triggered by the cytokine superfamily of receptors (e.g., the Interleukins, Interferons, GM-CSF, and Leptin).

Because of the wide range of known factors capable of stimulating tyrosine kinase activity, identifying whether polypeptide of the present invention or a molecule induced by polypeptide of the present invention is capable of activating tyrosine kinase signal transduction pathways is of interest. Therefore, the following protocol is designed to identify such molecules capable of activating the tyrosine kinase signal transduction pathways.

Seed target cells (e.g., primary keratinocytes) at a density of approximately 25,000 cells per well in a 96 well Loprodyne Silent Screen Plates purchased from Nalge Nunc (Naperville, Ill.). The plates are sterilized with two 30 minute rinses with 100% ethanol, rinsed with water and dried overnight. Some plates are coated for 2 hr with 100 ml of cell culture grade type I collagen (50 mg/ml), gelatin (2%) or polylysine (50 mg/ml), all of which can be purchased from Sigma Chemicals (St. Louis, Mo.) or 10% Matrigel purchased from Becton Dickinson (Bedford, Mass.), or calf serum, rinsed with PBS and stored at 4 degree C. Cell growth on these plates is assayed by seeding 5,000 cells/well in growth medium and indirect quantitation of cell number through use of alamarBlue as described by the manufacturer Alamar Biosciences, Inc. (Sacramento, Calif.) after 48 hr. Falcon plate covers #3071 from Becton Dickinson (Bedford, Mass.) are used to cover the Loprodyne Silent Screen Plates. Falcon Microtest III cell culture plates can also be used in some proliferation experiments.

To prepare extracts, A431 cells are seeded onto the nylon membranes of Loprodyne plates (20,000/200 ml/well) and cultured overnight in complete medium. Cells are quiesced by incubation in serum-free basal medium for 24 hr. After 5-20 minutes treatment with EGF (60 ng/ml) or 50 ul of the supernatant produced in Example 27, the medium was removed and 100 ml of extraction buffer ((20 mM HEPES pH 7.5, 0.15 M NaCl, 1% Triton X-100, 0.1% SDS, 2 mM Na3VO4, 2 mM Na4P207 and a cocktail of protease inhibitors (# 1836170) obtained from Boeheringer Mannheim (Indianapolis, Ind.)) is added to each well and the plate is shaken on a rotating shaker for 5 minutes at 4° C. The plate is then placed in a vacuum transfer manifold and the extract filtered through the 0.45 mm membrane bottoms of each well using house vacuum. Extracts are collected in a 96-well catch/assay plate in the bottom of the vacuum manifold and immediately placed on ice. To obtain extracts clarified by centrifugation, the content of each well, after detergent solubilization for 5 minutes, is removed and centrifuged for 15 minutes at 4 degree C. at 16,000×g.

Test the filtered extracts for levels of tyrosine kinase activity. Although many methods of detecting tyrosine kinase activity are known, one method is described here.

Generally, the tyrosine kinase activity of a supernatant is evaluated by determining its ability to phosphorylate a tyrosine residue on a specific substrate (a biotinylated peptide). Biotinylated peptides that can be used for this purpose include PSK1 (corresponding to amino acids 6-20 of the cell division kinase cdc2-p34) and PSK2 (corresponding to amino acids 1-17 of gastrin). Both peptides are substrates for a range of tyrosine kinases and are available from Boehringer Mannheim.

The tyrosine kinase reaction is set up by adding the following components in order. First, add 10 ul of 5 uM Biotinylated Peptide, then 10 ul ATP/Mg₂₊ (5 mM ATP/50 mM MgCl₂), then 10 ul of 5× Assay Buffer (40 mM imidazole hydrochloride, pH7.3, 40 mM beta-glycerophosphate, 1 mM EGTA, 100 mM MgCl₂, 5 mM MnCl₂, 0.5 mg/ml BSA), then 5 ul of Sodium Vanadate (1 mM), and then 5 ul of water. Mix the components gently and preincubate the reaction mix at 30 degree C. for 2 min. Initial the reaction by adding 10 ul of the control enzyme or the filtered supernatant.

The tyrosine kinase assay reaction is then terminated by adding 10 ul of 120 mm EDTA and place the reactions on ice.

Tyrosine kinase activity is determined by transferring 50 ul aliquot of reaction mixture to a microtiter plate (MTP) module and incubating at 37 degree C. for 20 min. This allows the streptavidin coated 96 well plate to associate with the biotinylated peptide. Wash the MTP module with 300 ul/well of PBS four times. Next add 75 ul of anti-phospotyrosine antibody conjugated to horse radish peroxidase (anti-P-Tyr-POD(0.5u/ml)) to each well and incubate at 37 degree C. for one hour. Wash the well as above.

Next add 100 ul of peroxidase substrate solution (Boehringer Mannheim) and incubate at room temperature for at least 5 mins (up to 30 min). Measure the absorbance of the sample at 405 nm by using ELISA reader. The level of bound peroxidase activity is quantitated using an ELISA reader and reflects the level of tyrosine kinase activity.

Example 35 High-Throughput Screening Assay Identifying Phosphorylation Activity

As a potential alternative and/or complement to the assay of protein tyrosine kinase activity described in Example 34, an assay which detects activation (phosphorylation) of major intracellular signal transduction intermediates can also be used. For example, as described below one particular assay can detect tyrosine phosphorylation of the Erk-1 and Erk-2 kinases. However, phosphorylation of other molecules, such as Raf, JNK, p38 MAP, Map kinase kinase (MEK), MEK kinase, Src, Muscle specific kinase (MuSK), IRAK, Tec, and Janus, as well as any other phosphoserine, phosphotyrosine, or phosphothreonine molecule, can be detected by substituting these molecules for Erk-1 or Erk-2 in the following assay.

Specifically, assay plates are made by coating the wells of a 96-well ELISA plate with 0.1 ml of protein G (1 ug/ml) for 2 hr at room temp, (RT). The plates are then rinsed with PBS and blocked with 3% BSA/PBS for 1 hr at RT. The protein G plates are then treated with 2 commercial monoclonal antibodies (10 ng/well) against Erk-1 and Erk-2 (1 hr at RT) (Santa Cruz Biotechnology). (To detect other molecules, this step can easily be modified by substituting a monoclonal antibody detecting any of the above described molecules.) After 3-5 rinses with PBS, the plates are stored at 4 degree C. until use.

A431 cells are seeded at 20,000/well in a 96-well Loprodyne filterplate and cultured overnight in growth medium. The cells are then starved for 48 hr in basal medium (DMEM) and then treated with EGF (6 ng/well) or 50 ul of the supernatants obtained in Example 27 for 5-20 minutes. The cells are then solubilized and extracts filtered directly into the assay plate.

After incubation with the extract for 1 hr at RT, the wells are again rinsed. As a positive control, a commercial preparation of MAP kinase (10 ng/well) is used in place of A431 extract. Plates are then treated with a commercial polyclonal (rabbit) antibody (1 ug/ml) which specifically recognizes the phosphorylated epitope of the Erk-1 and Erk-2 kinases (1 hr at RT). This antibody is biotinylated by standard procedures. The bound polyclonal antibody is then quantitated by successive incubations with Europium-streptavidin and Europium fluorescence enhancing reagent in the Wallac DELFIA instrument (time-resolved fluorescence). An increased fluorescent signal over background indicates a phosphorylation by polypeptide of the present invention or a molecule induced by polypeptide of the present invention.

Example 36 Assay for the Stimulation of Bone Marrow CD34+Cell Proliferation

This assay is based on the ability of human CD34+ to proliferate in the presence of hematopoietic growth factors and evaluates the ability of isolated polypeptides expressed in mammalian cells to stimulate proliferation of CD34+cells.

It has been previously shown that most mature precursors will respond to only a single signal. More immature precursors require at least two signals to respond. Therefore, to test the effect of polypeptides on hematopoietic activity of a wide range of progenitor cells, the assay contains a given polypeptide in the presence or absence of other hematopoietic growth factors. Isolated cells are cultured for 5 days in the presence of Stem Cell Factor (SCF) in combination with tested sample. SCF alone has a very limited effect on the proliferation of bone marrow (BM) cells, acting in such conditions only as a “survival” factor. However, combined with any factor exhibiting stimulatory effect on these cells (e.g., IL-3), SCF will cause a synergistic effect. Therefore, if the tested polypeptide has a stimulatory effect on hematopoietic progenitors, such activity can be easily detected. Since normal BM cells have a low level of cycling cells, it is likely that any inhibitory effect of a given polypeptide, or agonists or antagonists thereof, might not be detected. Accordingly, assays for an inhibitory effect on progenitors is preferably tested in cells that are first subjected to in vitro stimulation with SCF+IL+3, and then contacted with the compound that is being evaluated for inhibition of such induced proliferation.

Briefly, CD34+cells are isolated using methods known in the art. The cells are thawed and resuspended in medium (QBSF 60 serum-free medium with 1% L-glutamine (500 ml) Quality Biological, Inc., Gaithersburg, Md. Cat# 160-204-101). After several gentle centrifugation steps at 200×g, cells are allowed to rest for one hour. The cell count is adjusted to 2.5×10⁵ cells/ml. During this time, 100 μl of sterile water is added to the peripheral wells of a 96-well plate. The cytokines that can be tested with a given polypeptide in this assay is rhSCF (R&D Systems, Minneapolis, Minn., Cat# 255-SC) at 50 ng/ml alone and in combination with rhSCF and rhIL-3 (R&D Systems, Minneapolis, Minn., Cat# 203-ML) at 30 ng/ml. After one hour, 10 μl of prepared cytokines, 50 μl of the supernatants prepared in Example 27 (supernatants at 1:2 dilution=50 μl) and 20 μl of diluted cells are added to the media which is already present in the wells to allow for a final total volume of 100 μl. The plates are then placed in a 37° C./5% CO₂ incubator for five days.

Eighteen hours before the assay is harvested, 0.5 μCi/well of [3H] Thymidine is added in a 10 μl volume to each well to determine the proliferation rate. The experiment is terminated by harvesting the cells from each 96-well plate to a filtermat using the Tomtec Harvester 96. After harvesting, the filtermats are dried, trimmed and placed into OmniFilter assemblies consisting of one OmniFilter plate and one OmniFilter Tray. 60 μl Microscint is added to each well and the plate sealed with TopSeal-A press-on sealing film A bar code 15 sticker is affixed to the first plate for counting. The sealed plates are then loaded and the level of radioactivity determined via the Packard Top Count and the printed data collected for analysis. The level of radioactivity reflects the amount of cell proliferation.

The studies described in this example test the activity of a given polypeptide to stimulate bone marrow CD34+cell proliferation. One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof. As a nonlimiting example, potential antagonists tested in this assay would be expected to inhibit cell proliferation in the presence of cytokines and/or to increase the inhibition of cell proliferation in the presence of cytokines and a given polypeptide. In contrast, potential agonists tested in this assay would be expected to enhance cell proliferation and/or to decrease the inhibition of cell proliferation in the presence of cytokines and a given polypeptide.

The ability of a gene to stimulate the proliferation of bone marrow CD34+cells indicates that polynucleotides and polypeptides corresponding to the gene are useful for the detection, prevention, diagnosis, prognostication, treatment, and/or amelioration of disorders affecting the immune system and hematopoiesis. Representative uses are described in the “Immune Activity” and “Infectious Disease” sections above, and elsewhere herein.

Example 37 Assay for Extracellular Matrix Enhanced Cell Response (EMECR)

The objective of the Extracellular Matrix Enhanced Cell Response (EMECR) assay is to identify gene products (e.g., isolated polypeptides) that act on the hematopoietic stem cells in the context of the extracellular matrix (ECM) induced signal.

Cells respond to the regulatory factors in the context of signal(s) received from the surrounding microenvironment. For example, fibroblasts, and endothelial and epithelial stem cells fail to replicate in the absence of signals from the ECM. Hematopoietic stem cells can undergo self-renewal in the bone marrow, but not in in vitro suspension culture. The ability of stem cells to undergo self-renewal in vitro is dependent upon their interaction with the stromal cells and the ECM protein fibronectin (fn). Adhesion of cells to fn is mediated by the α₅.β₁ and α₄.β₁ integrin receptors, which are expressed by human and mouse hematopoietic stem cells. The factor(s) which integrate with the ECM environment and are responsible for stimulating stem cell self-renewal have a not yet been identified. Discovery of such factors should be of great interest in gene therapy and bone marrow transplant applications

Briefly, polystyrene, non tissue culture treated, 96-well plates are coated with fn fragment at a coating concentration of 0.2 μg/cm². Mouse bone marrow cells are plated (1,000 cells/well) in 0.2 ml of serum-free medium. Cells cultured in the presence of IL-3 (5 ng/ml)+SCF (50 ng/ml) would serve as the positive control, conditions under which little self-renewal but pronounced differentiation of the stem cells is to be expected. Gene products of the invention (e.g., including, but not limited to, polynucleotides and polypeptides of the present invention, and supernatants produced in Example 27), are tested with appropriate negative controls in the presence and absence of SCF(5.0 ng/ml), where test factor supernatants represent 10% of the total assay volume. The plated cells are then allowed to grow by incubating in a low oxygen environment (5% CO₂, 7% O₂, and 88% N₂) tissue culture incubator for 7 days. The number of proliferating cells within the wells is then quantitated by measuring thymidine incorporation into cellular DNA. Verification of the positive hits in the assay will require phenotypic characterization of the cells, which can be accomplished by scaling up of the culture system and using appropriate antibody reagents against cell surface antigens and FACScan.

One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.

If a particular polypeptide of the present invention is found to be a stimulator of hematopoietic progenitors, polynucleotides and polypeptides corresponding to the gene encoding said polypeptide may be useful for the detection, prevention, diagnosis, prognostication, treatment, and/or amelioration of disorders affecting the immune system and hematopoiesis. Representative uses are described in the “Immune Activity” and “Infectious Disease” sections above, and elsewhere herein. The gene product may also be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.

Additionally, the polynucleotides and/or polypeptides of the gene of interest and/or agonists and/or antagonists thereof, may also be employed to inhibit the proliferation and differentiation of hematopoietic cells and therefore may be employed to protect bone marrow stem cells from chemotherapeutic agents during chemotherapy. This antiproliferative effect may allow administration of higher doses of chemotherapeutic agents and, therefore, more effective chemotherapeutic treatment.

Moreover, polynucleotides and polypeptides corresponding to the gene of interest may also be useful for the detection, prevention, diagnosis, prognostication, treat, and/or amelioration of hematopoietic and hematologic related disorders such as, for example, anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex-vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia

Example 38 Human Dermal Fibroblast and Aortic Smooth Muscle Cell Proliferation

The polypeptide of interest is added to cultures of normal human dermal fibroblasts (NHDF) and human aortic smooth muscle cells (AOSMC) and two co-assays are performed with each sample. The first assay examines the effect of the polypeptide of interest on the proliferation of normal human dermal fibroblasts (NHDF) or aortic smooth muscle cells (AoSMC). Aberrant growth of fibroblasts or smooth muscle cells is a part of several pathological processes, including fibrosis, and restenosis. The second assay examines IL6 production by both NHDF and SMC. IL6 production is an indication of functional activation. Activated cells will have increased production of a number of cytokines and other factors, which can result in a proinflammatory or immunomodulatory outcome. Assays are run with and without co-TNFa stimulation, in order to check for costimulatory or inhibitory activity.

Briefly, on day 1,96-well black plates are set up with 1000 cells/well (NHDF) or 2000 cells/well (AoSMC) in 100 μl culture media. NHDF culture media contains: Clonetics FB basal media, 1 mg/ml hFGF, 5 mg/ml insulin, 50 mg/ml gentamycin, 2% FBS, while AoSMC culture media contains Clonetics SM basal media, 0.5 μg/ml hEGF, 5 mg/ml insulin, 1 μg/ml hFGF, 50 mg/ml gentamycin, 50 μg/ml Amphotericin B, 5% FBS. After incubation at 37° C. for at least 4-5 hours culture media is aspirated and replaced with growth arrest media. Growth arrest media for NHDF contains fibroblast basal media, 50 mg/ml gentamycin, 2% FBS, while growth arrest media for AOSMC contains SM basal media, 50 mg/ml gentamycin, 50 μg/ml Amphotericin B, 0.4% FBS. Incubate at 37° C. until day 2.

On day 2, serial dilutions and templates of the polypeptide of interest are designed such that they always include media controls and known-protein controls. For both stimulation and inhibition experiments, proteins are diluted in growth arrest media. For inhibition experiments, TNFa is added to a final concentration of 2 ng/ml (NHDF) or 5 ng/ml (AoSMC). Add ⅓ vol media containing controls or polypeptides of the present invention and incubate at 37 degrees C./5% CO₂ until day 5.

Transfer 60 μl from each well to another labeled 96-well plate, cover with a plate-sealer, and store at 4 degrees C. until Day 6 (for IL6 ELISA). To the remaining 100 μl in the cell culture plate, aseptically add Alamar Blue in an amount equal to 10% of the culture volume (10 μl). Return plates to incubator for 3 to 4 hours. Then measure fluorescence with excitation at 530 nm and emission at 590 nm using the CytoFluor. This yields the growth stimulation/inhibition data.

On day 5, the IL6 ELISA is performed by coating a 96 well plate with 50-100 ul/well of Anti-Human IL6 Monoclonal antibody diluted in PBS, pH 7.4, incubate ON at room temperature.

On day 6, empty the plates into the sink and blot on paper towels. Prepare Assay Buffer containing PBS with 4% BSA. Block the plates with 200 μl/well of Pierce Super Block blocking buffer in PBS for 1-2 hr and then wash plates with wash buffer (PBS, 0.05% Tween-20). Blot plates on paper towels. Then add 50 μl/well of diluted Anti-Human IL-6 Monoclonal, Biotin-labeled antibody at 0.50 mg/ml. Make dilutions of IL-6 stock in media (30, 10, 3, 1, 0.3, 0 ng/ml). Add duplicate samples to top row of plate. Cover the plates and incubate for 2 hours at RT on shaker.

Plates are washed with wash buffer and blotted on paper towels. Dilute EU-labeled Streptavidin 1:1000 in Assay buffer, and add 100 μl/well. Cover the plate and incubate 1 h at RT. Plates are again washed with wash buffer and blotted on paper towels.

Add 100 μl/well of Enhancement Solution. Shake for 5 minutes. Read the plate on the Wallac DELFIA Fluorometer. Readings from triplicate samples in each assay were tabulated and averaged.

A positive result in this assay suggests AoSMC cell proliferation and that the polypeptide of the present invention may be involved in dermal fibroblast proliferation and/or smooth muscle cell proliferation. A positive result also suggests many potential uses of polypeptides, polynucleotides, agonists and/or antagonists of the polynucleotide/polypeptide of the present invention which gives a positive result. For example, inflammation and immune responses, wound healing, and angiogenesis, as detailed throughout this specification. Particularly, polypeptides of the present invention and polynucleotides of the present invention may be used in wound healing and dermal regeneration, as well as the promotion of vasculogenesis, both of the blood vessels and lymphatics. The growth of vessels can be used in the treatment of, for example, cardiovascular diseases. Additionally, antagonists of polypeptides and polynucleotides of the invention may be useful in treating diseases, disorders, and/or conditions which involve angiogenesis by acting as an anti-vascular agent (e.g., anti-angiogenesis). These diseases, disorders, and/or conditions are known in the art and/or are described herein, such as, for example, malignancies, solid tumors, benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; artheroscleric plaques; ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, uvietis and Pterygia (abnormal blood vessel growth) of the eye; rheumatoid arthritis; psoriasis; delayed wound healing; endometriosis; vasculogenesis; granulations; hypertrophic scars (keloids); nonunion fractures; scleroderima; trachoma; vascular adhesions; myocardial angiogenesis; coronary collaterals; cerebral collaterals; arteriovenous malformations; ischemic limb angiogenesis; Osler-Webber Syndrome; plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; fibromuscular dysplasia; wound granulation; Crohn's disease; and atherosclerosis. Moreover, antagonists of polypeptides and polynucleotides of the invention may be useful in treating anti-hyperproliferative diseases and/or anti-inflammatory known in the art and/or described herein.

One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.

Example 39 Cellular Adhesion Molecule (CAM) Expression on Endothelial Cells

The recruitment of lymphocytes to areas of inflammation and angiogenesis involves specific receptor-ligand interactions between cell surface adhesion molecules (CAMs) on lymphocytes and the vascular endothelium The adhesion process, in both normal and pathological settings, follows a multi-step cascade that involves intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) expression on endothelial cells (EC). The expression of these molecules and others on the vascular endothelium determines the efficiency with which leukocytes may adhere to the local vasculature and extravasate into the local tissue during the development of an inflammatory response. The local concentration of cytokines and growth factor participate in the modulation of the expression of these CAMs.

Briefly, endothelial cells (e.g., Human Umbilical Vein Endothelial cells (HUVECs)) are grown in a standard 96 well plate to confluence, growth medium is removed from the cells and replaced with 100 μl of 199 Medium (10% fetal bovine serum (FBS)). Samples for testing and positive or negative controls are added to the plate in triplicate (in 10 μl volumes). Plates are then incubated at 37° C. for either 5 h (selectin and integrin expression) or 24 h (integrin expression only). Plates are aspirated to remove medium and 100 μl of 0.1% paraformaldehyde-PBS (with Ca++ and Mg++) is added to each well. Plates are held at 4° C. for 30 min. Fixative is removed from the wells and wells are washed 1× with PBS(+Ca, Mg)+0.5% BSA and drained. 10 μl of diluted primary antibody is added to the test and control wells. Anti-ICAM-1-Biotin, Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at a concentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stock antibody). Cells are incubated at 37° C. for 30 min. in a humidified environment. Wells are washed three times with PBS(+Ca, Mg)+0.5% BSA. 20 μl of diluted ExtrAvidin-Alkaline Phosphatase (1:5,000 dilution, referred to herein as the working dilution) are added to each well and incubated at 37° C. for 30 min. Wells are washed three times with PBS(+Ca, Mg)+0.5% BSA. Dissolve 1 tablet of p-Nitrophenol Phosphate pNPP per 5 ml of glycine buffer (pH 10.4). 100 μl of pNPP substrate in glycine buffer is added to each test well. Standard wells in triplicate are prepared from the working dilution of the ExtrAvidin-Alkaline Phosphotase in glycine buffer: 1:5,000 (10⁰)>10^(−0.5)>10⁻¹>10^(−1.5) 0.5 μl of each dilution is added to triplicate wells and the resulting AP content in each well is 5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent is then added to each of the standard wells. The plate is incubated at 37° C. for 4 h. A volume of 50 μl of 3M NaOH is added to all wells. The plate is read on a plate reader at 405 nm using the background subtraction option on blank wells filled with glycine buffer only. Additionally, the template is set up to indicate the concentration of AP-conjugate in each standard well [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated as amount of bound AP-conjugate in each sample.

Example 40 Alamar Blue Endothelial Cells Proliferation Assay

This assay may be used to quantitatively determine protein mediated inhibition of bFGF-induced proliferation of Bovine Lymphatic Endothelial Cells (LECs), Bovine Aortic Endothelial Cells (BAECs) or Human Microvascular Uterine Myometrial Cells (UTMECs). This assay incorporates a fluorometric growth indicator based on detection of metabolic activity. A standard Alamar Blue Proliferation Assay is prepared in EGM-2MV with 10 ng/ml of bFGF added as a source of endothelial cell stimulation. This assay may be used with a variety of endothelial cells with slight changes in growth medium and cell concentration. Dilutions of the protein batches to be tested are diluted as appropriate. Serum-free medium (GIBCO SFM) without bFGF is used as a non-stimulated control and Angiostatin or TSP-1 are included as a known inhibitory controls.

Briefly, LEC, BAECs or UTMECs are seeded in growth media at a density of 5000 to 2000 cells/well in a 96 well plate and placed at 37 degreesC overnight After the overnight incubation of the cells, the growth media is removed and replaced with GIBCO EC-SFM. The cells are treated with the appropriate dilutions of the protein of interest or control protein sample(s) (prepared in SFM) in triplicate wells with additional bFGF to a concentration of 10 ng/ml. Once the cells have been treated with the samples, the plate(s) is/are placed back in the 37° C. incubator for three days. After three days 10 ml of stock alarnar blue (Biosource Cat# DAL1100) is added to each well and the plate(s) is/are placed back in the 37° C. incubator for four hours. The plate(s) are then read at 530 nm excitation and 590 nm emission using the CytoFluor fluorescence reader. Direct output is recorded in relative fluorescence units.

Alamar blue is an oxidation-reduction indicator that both fluoresces and changes color in response to chemical reduction of growth medium resulting from cell growth. As cells grow in culture, innate metabolic activity results in a chemical reduction of the immediate surrounding environment. Reduction related to growth causes the indicator to change from oxidized (non-fluorescent blue) form to reduced (fluorescent red) form (i.e., stimulated proliferation will produce a stronger signal and inhibited proliferation will produce a weaker signal and the total signal is proportional to the total number of cells as well as their metabolic activity). The background level of activity is observed with the starvation medium alone. This is compared to the output observed from the positive control samples (bFGF in growth medium) and protein dilutions.

Example 41 Detection of Inhibition of a Mixed Lymphocyte Reaction

This assay can be used to detect and evaluate inhibition of a Mixed Lymphocyte Reaction (MLR) by gene products (e.g., isolated polypeptides). Inhibition of a MLR may be due to a direct effect on cell proliferation and viability, modulation of costimulatory molecules on interacting cells, modulation of adhesiveness between lymphocytes and accessory cells, or modulation of cytokine production by accessory cells. Multiple cells may be targeted by these polypeptides since the peripheral blood mononuclear fraction used in this assay includes T, B and natural killer lymphocytes, as well as monocytes and dendritic cells.

Polypeptides of interest found to inhibit the MLR may find application in diseases associated with lymphocyte and monocyte activation or proliferation. These include, but are not limited to, diseases such as asthma, arthritis, diabetes, inflammatory skin conditions, psoriasis, eczema, systemic lupus erythematosus, multiple sclerosis, glomerulonephritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, arteriosclerosis, cirrhosis, graft vs. host disease, host vs. graft disease, hepatitis, leukemia and lymphoma.

Briefly, PBMCs from human donors are purified by density gradient centrifugation using Lymphocyte Separation Medium (LSM®, density 1.0770 g/ml, Organon Teknika Corporation, West Chester, Pa.). PBMCs from two donors are adjusted to 2×10⁶ cells/ml in RPMI-1640 (Life Technologies, Grand Island, N.Y.) supplemented with 10% FCS and 2 mM glutamine. PBMCs from a third donor is adjusted to 2×10⁵ cells/ml. Fifty microliters of PBMCs from each donor is added to wells of a 96-well round bottom microtiter plate. Dilutions of test materials (50 μl) is added in triplicate to microtiter wells. Test samples (of the protein of interest) are added for final dilution of 1:4; rhuIL-2 (R&D Systems, Minneapolis, Minn., catalog number 202-IL) is added to a final concentration of 1 μg/ml; anti-CD4 mAb (R&D Systems, clone 34930.11, catalog number MAB379) is added to a final concentration of 10 μg/ml. Cells are cultured for 7-8 days at 37° C. in 5% CO₂, and 1 μC of [³H] thymidine is added to wells for the last 16 hrs of culture. Cells are harvested and thymidine incorporation determined using a Packard TopCount. Data is expressed as the mean and standard deviation of triplicate determinations.

Samples of the protein of interest are screened in separate experiments and compared to the negative control treatment, anti-CD4 mAb, which inhibits proliferation of lymphocytes and the positive control treatment, IL-2 (either as recombinant material or supernatant), which enhances proliferation of lymphocytes.

One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.

Example 42 Assays for Protease Activity

The following assay may be used to assess protease activity of the polypeptides of the invention.

Gelatin and casein zymography are performed essentially as described (Heusen et al., Anal. Biochem., 102:196-202 (1980); Wilson et al., Journal of Urology, 149:653-658 (1993)). Samples are run on 10% polyacryamide/0.1% SDS gels containing 1% gelain orcasein, soaked in 2.5% triton at room temperature for 1 hour, and in 0.1M glycine, pH 8.3 at 37° C. 5 to 16 hours. After staining in amido black areas of proteolysis apear as clear areas agains the blue-black background. Trypsin (Sigma T8642) is used as a positive control.

Protease activity is also determined by monitoring the cleavage of n-a-benzoyl-L-arginine ethyl ester (BABE) (Sigma B-4500. Reactions are set up in (25 mMNaPO₄, 1 mM EDTA, and 1 mM BAEE), pH 7.5. Samples are added and the change in adsorbance at 260 nm is monitored on the Beckman DU-6 spectrophotometer in the time-drive mode. Trypsin is used as a positive control.

Additional assays based upon the release of acid-soluble peptides from casein or hemoglobin measured as adsorbance at 280 nm or colorimetrically using the Folin method are performed as described in Bergmeyer, et al., Methods of Enzymatic Analysis, 5 (1984). Other assays involve the solubilization of chromogenic substrates (Ward, Applied Science, 251-317 (1983)).

Example 43 Identifying Serine Protease Substrate Specificity

Methods known in the art or described herein may be used to determine the substrate specificity of the polypeptides of the present invention having serine protease activity. A preferred method of determining substrate specificity is by the use of positional scanning synthetic combinatorial libraries as described in GB 2 324 529 (incorporated herein in its entirety).

Example 44 Ligand Binding Assays

The following assay may be used to assess ligand binding activity of the polypeptides of the invention.

Ligand binding assays provide a direct method for ascertaining receptor pharmacology and are adaptable to a high throughput format. The purified ligand for a polypeptide is radiolabeled to high specific activity (50-2000 Ci/mmol) for binding studies. A determination is then made that the process of radiolabeling does not diminish the activity of the ligand towards its polypeptide. Assay conditions for buffers, ions, pH and other modulators such as nucleotides are optimized to establish a workable signal to noise ratio for both membrane and whole cell polypeptide sources. For these assays, specific polypeptide binding is defined as total associated radioactivity minus the radioactivity measured in the presence of an excess of unlabeled competing ligand. Where possible, more than one competing ligand is used to define residual nonspecific binding.

Example 45 Functional Assay in Xenopus Oocytes

Capped RNA transcripts from linearized plasmid templates encoding the polypeptides of the invention are synthesized in vitro with RNA polymerases in accordance with standard procedures. In vitro transcripts are suspended in water at a final concentration of 0.2 mg/ml. Ovarian lobes are removed from adult female toads, Stage V defolliculated oocytes are obtained, and RNA transcripts (10 ng/oocytc) are injected in a 50 nl bolus using a microinjection apparatus. Two electrode voltage clamps are used to measure the currents from individual Xenopus oocytes in response polypeptides and polypeptide agonist exposure. Recordings are made in Ca2+ free Barth's medium at room temperature. The Xenopus system can be used to screen known ligands and tissue/cell extracts for activating ligands.

Example 46 Microphysiometric Assays

Activation of a wide variety of secondary messenger systems results in extrusion of small amounts of acid from a cell. The acid formed is largely as a result of the increased metabolic activity required to fuel the intracellular signaling process. The pH changes in the media surrounding the cell are very small but are detectable by the CYTOSENSOR microphysiometer (Molecular Devices Ltd., Menlo Park, Calif.). The CYTOSENSOR is thus capable of detecting the activation of polypeptide which is coupled to an energy utilizing intracellular signaling pathway.

Example 47 Extract/Cell Supernatant Screening

A large number of mammalian receptors exist for which there remains, as yet, no cognate activating ligand (agonist). Thus, active ligands for these receptors may not be included within the ligands banks as identified to date. Accordingly, the polypeptides of the invention can also be functionally screened (using calcium, cAMP, microphysiometer, oocyte electrophysiology, etc., functional screens) against tissue extracts to identify its natural ligands. Extracts that produce positive functional responses can be sequentially subfractionated until an activating ligand is isolated and identified.

Example 48 Calcium and cAMP Functional Assays

Seven transmembrane receptors which are expressed in HEK 293 cells have been shown to be coupled functionally to activation of PLC and calcium mobilization and/or cAMP stimulation or inhibition. Basal calcium levels in the HEK 293 cells in receptor-transfected or vector control cells were observed to be in the normal, 100 nM to 200 nM, range. HEK 293 cells expressing recombinant receptors are loaded with fura 2 and in a single day >150 selected ligands or tissue/cell extracts are evaluated for agonist induced calcium mobilization. Similarly, HEK 293 cells expressing recombinant receptors are evaluated for the stimulation or inhibition of cAMP production using standard cAMP quantitation assays. Agonists presenting a calcium transient or cAMP fluctuation are tested in vector control cells to determine if the response is unique to the transfected cells expressing receptor.

Example 49 ATP-Binding Assay

The following assay may be used to assess ATP-binding activity of polypeptides of the invention.

ATP-binding activity of the polypeptides of the invention may be detected using the ATP-binding assay described in U.S. Pat. No. 5,858,719, which is herein incorporated by reference in its entirety. Briefly, ATP-binding to polypeptides of the invention is measured via photoaffinity labeling with 8-azido-ATP in a competition assay. Reaction mixtures containing 1 mg/ml of the ABC transport protein of the present invention are incubated with varying concentrations of ATP, or the non-hydrolyzable ATP analog adenyl-5′-imidodiphosphate for 10 minutes at 4° C. A mixture of 8-azido-ATP (Sigma Chem. Corp., St. Louis, Mo.) plus 8-azido-ATP (³²P-ATP) (5 mCi/μmol, ICN, Irvine Calif.) is added to a final concentration of 100 μM and 0.5 ml aliquots are placed in the wells of a porcelain spot plate on ice. The plate is irradiated using a short wave 254 nm UV lamp at a distance of 2.5 cm from the plate for two one-minute intervals with a one-minute cooling interval in between. The reaction is stopped by addition of dithiothreitol to a final concentration of 2 mM. The incubations are subjected to SDS-PAGE electrophoresis, dried, and autoradiographed. Protein bands corresponding to the particular polypeptides of the invention are excised, and the radioactivity quantified. A decrease in radioactivity with increasing ATP or adenly-5′-imidodiphosphate provides a measure of ATP affinity to the polypeptides.

Example 50 Small Molecule Screening

This invention is particularly useful for screening therapeutic compounds by using the polypeptides of the invention, or binding fragments thereof, in any of a variety of drug screening techniques. The polypeptide or fragment employed in such a test may be affixed to a solid support, expressed on a cell surface, free in solution, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. One may measure, for example, the formulation of complexes between the agent being tested and polypeptide of the invention.

Thus, the present invention provides methods of screening for drugs or any other agents which affect activities mediated by the polypeptides of the invention. These methods comprise contacting such an agent with a polypeptide of the invention or fragment thereof and assaying for the presence of a complex between the agent and the polypeptide or fragment thereof, by methods well known in the art. In such a competitive binding assay, the agents to screen are typically labeled. Following incubation, free agent is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of a particular agent to bind to the polypeptides of the invention.

Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to the polypeptides of the invention, and is described in great detail in European Patent Application 84/03564, published on Sep. 13, 1984, which is herein incorporated by reference in its entirety. Briefly stated, large numbers of different small molecule test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The test compounds are reacted with polypeptides of the invention and washed. Bound polypeptides are then detected by methods well known in the art. Purified polypeptides are coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies may be used to capture the peptide and immobilize it on the solid support.

This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding polypeptides of the invention specifically compete with a test compound for binding to the polypeptides or fragments thereof. In this manner, the antibodies are used to detect the presence of any peptide which shares one or more antigenic epitopes with a polypeptide of the invention.

Example 51 Phosphorylation Assay

In order to assay for phosphorylation activity of the polypeptides of the invention, a phosphorylation assay as described in U.S. Pat. No. 5,958,405 (which is herein incorporated by reference) is utilized. Briefly, phosphorylation activity may be measured by phosphorylation of a protein substrate using gamma-labeled ³²P-ATP and quantitation of the incorporated radioactivity using a gamma radioisotope counter. The polypeptides of the invention are incubated with the protein substrate, ³²P-ATP, and a kinase buffer. The ³²P incorporated into the substrate is then separated from free ³²P-ATP by electrophoresis, and the incorporated ³²P is counted and compared to a negative control. Radioactivity counts above the negative control are indicative of phosphorylation activity of the polypeptides of the invention.

Example 52 Detection of Phosphorylation Activity (Activation) of the Polypeptides of the Invention in the Presence of Polypeptide Ligands

Methods known in the art or described herein may be used to determine the phosphorylation activity of the polypeptides of the invention. A preferred method of determining phosphorylation activity is by the use of the tyrosine phosphorylation assay as described in U.S. Pat. No. 5,817,471 (incorporated herein by reference).

Example 53 Identification of Signal Transduction Proteins that Interact with Polypeptides of the Present Invention

The purified polypeptides of the invention are research tools for the identification, characterization and purification of additional signal transduction pathway proteins or receptor proteins. Briefly, labeled polypeptides of the invention are useful as reagents for the purification of molecules with which it interacts. In one embodiment of affinity purification, polypeptides of the invention are covalently coupled to a chromatography column. Cell-free extract derived from putative target cells, such as carcinoma tissues, is passed over the column, and molecules with appropriate affinity bind to the polypeptides of the invention. The protein complex is recovered from the column, dissociated, and the recovered molecule subjected to N-terminal protein sequencing. This amino acid sequence is then used to identify the captured molecule or to design degenerate oligonucleotide probes for cloning the relevant gene from an appropriate cDNA library.

Example 54 IL-6 Bioassay

To test the proliferative effects of the polypeptides of the invention, the IL-6 Bioassay as described by Marz et al. is utilized (Proc. Natl. Acad. Sci., U.S.A., 95:3251-56 (1998), which is herein incorporated by reference). Briefly, IL-6 dependent B9 murine cells are washed three times in IL-6 free medium and plated at a concentration of 5,000 cells per well in 50 μl, and 50 μl of the IL-6-like polypeptide is added. After 68 hrs. at 37° C., the number of viable cells is measured by adding the tetrazolium salt thiazolyl blue (MTT) and incubating for a further 4 hrs. at 37° C. B9 cells are lysed by SDS and optical density is measured at 570 nm. Controls containing IL-6 (positive) and no cytokine (negative) are utilized. Enhanced proliferation in the test sample(s) relative to the negative control is indicative of proliferative effects mediated by polypeptides of the invention.

Example 55 Assay for Phosphatase Activity

The following assay may be used to assess serine/threonine phosphatase (PTPase) activity of the polypeptides of the invention.

In order to assay for serine/threonine phosphatase (PTPase) activity, assays can be utilized which are widely known to those skilled in the art. For example, the serine/threonine phosphatase (PSPase) activity is measured using a PSPase assay kit from New England Biolabs, Inc. Myelin basic protein (MyBP), a substrate for PSPase, is phosphorylated on serine and threonine residues with cAMP-dependent Protein Kinase in the presence of [³²P]ATP. Protein serine/threonine phosphatase activity is then determined by measuring the release of inorganic phosphate from 32P-labeled MyBP.

Example 56 Interaction of Serine/Threonine Phosphatases with Other Proteins

The polypeptides of the invention with serine/threonine phosphatase activity as determined in Example 58 are research tools for the identification, characterization and purification of additional interacting proteins or receptor proteins, or other signal transduction pathway proteins. Briefly, labeled polypeptide(s) of the invention is useful as a reagent for the purification of molecules with which it interacts. In one embodiment of affinity purification, polypeptide of the invention is covalently coupled to a chromatography column. Cell-free extract derived from putative target cells, such as neural or liver cells, is passed over the column, and molecules with appropriate affinity bind to the polypeptides of the invention. The polypeptides of the invention-complex is recovered from the column, dissociated, and the recovered molecule subjected to N-terminal protein sequencing. This amino acid sequence is then used to identify the captured molecule or to design degenerate oligonucleotide probes for cloning the relevant gene from an appropriate cDNA library.

Example 57 Assaying for Heparanase Activity

In order to assay for heparanase activity of the polypeptides of the invention, the heparanase assay described by Vlodavsky et al is utilized (Vlodavsky, I., et al., Nat. Med., 5:793-802 (1999)). Briefly, cell lysates, conditioned media or intact cells (1×10⁶ cells per 35-mm dish) are incubated for 18 hrs at 37° C., pH 6.2-6.6, with ³⁵S-labeled ECM or soluble ECM derived peak I proteoglycans. The incubation medium is centrifuged and the supernatant is analyzed by gel filtration on a Sepharose CL-6B column (0.9×30 cm). Fractions are eluted with PBS and their radioactivity is measured. Degradation fragments of heparan sulfate side chains are eluted from Sepharose 6B at 0.5<K_(av)<0.8 (peak II). Each experiment is done at least three times. Degradation fragments corresponding to “peak II,” as described by Vlodavsky et al., is indicative of the activity of the polypeptides of the invention in cleaving heparan sulfate.

Example 58 Immobilization of Biomolecules

This example provides a method for the stabilization of polypeptides of the invention in non-host cell lipid bilayer constucts (see, e.g., Bieri et al., Nature Biotech 17:1105-1108 (1999), hereby incorporated by reference in its entirety herein) which can be adapted for the study of polypeptides of the invention in the various functional assays described above. Briefly, carbohydrate-specific chemistry for biotinylation is used to confine a biotin tag to the extracellular domain of the polypeptides of the invention, thus allowing uniform orientation upon immobilization. A 50 uM solution of polypeptides of the invention in washed membranes is incubated with 20 mM NaIO4 and 1.5 mg/ml (4 mM) BACH or 2 mg/ml (7.5 mM) biotin-hydrazide for 1 hr at room temperature (reaction volume, 150 ul). Then the sample is dialyzed (Pierce Slidealizer Cassett, 10 kDa cutoff; Pierce Chemical Co., Rockford Ill.) at 4 C first for 5 h, exchanging the buffer after each hour, and finally for 12 h against 500 ml buffer R (0.15 M NaCl, 1 mM MgC12, 10 mM sodium phosphate, pH7). Just before addition into a cuvette, the sample is diluted 1:5 in buffer ROG50 (Buffer R supplemented with 50 mM octylglucoside).

Example 59 TAQMAN

Quantitative PCR (QPCR). Total RNA from cells in culture are extracted by Trizol separation as recommended by the supplier (LifeTechnologies). (Total RNA is treated with DNase I (Life Technologies) to remove any contaminating genomic DNA before reverse transcription.) Total RNA (50 ng) is used in a one-step, 50 ul, RT-QPCR, consisting of Taqman Buffer A (Perkin-Elmer; 50 mM KCl/10 mM Tris, pH 8.3), 5.5 mM MgCl₂, 240 μM each dNTP, 0.4 units RNase inhibitor (Promega), 8% glycerol, 0.012% Tween-20, 0.05% gelatin, 0.3 uM primers, 0.1 uM probe, 0.025 units Amplitaq Gold (Perkin-Elmer) and 2.5 units Superscript II reverse transcriptase (Life Technologies). As a control for genomic contamination, parallel reactions are setup without reverse transcriptase. The relative abundance of (unknown) and 18S RNAs are assessed by using the Applied Biosystems Prism 7700 Sequence Detection System (Livak, K. J., Flood, S. J., Marmaro, J., Giusti, W. & Deetz, K. (1995) PCR Methods Appl. 4, 357-362). Reactions are carried out at 48° C. for 30 min, 95° C. for 10 min, followed by 40 cycles of 95° C. for 15 s, 60° C. for 1 min. Reactions are performed in triplicate.

Primers (f & r) and FRET probes sets are designed using Primer Express Software (Perkin-Elmer). Probes are labeled at the 5′-end with the reporter dye 6-FAM and on the 3′-end with the quencher dye TAMRA (Biosource International, Camarillo, Calif. or Perkin-Elmer).

Example 60 Assays for Metalloproteinase Activity

Metalloproteinases (EC 3.4.24.-) are peptide hydrolases which use metal ions, such as Zn²⁺, as the catalytic mechanism. Metalloproteinase activity of polypeptides of the present invention can be assayed according to the following methods.

Proteolysis of Alpha-2-Macroglobulin

To confirm protease activity, purified polypeptides of the invention are mixed with the substrate alpha-2-macroglobulin (0.2 unit/ml; Boehringer Mannheim, Germany) in 1× assay buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl, 10 mM CaCl₂, 25 μM ZnCl₂ and 0.05% Brij-35) and incubated at 37° C. for 1-5 days. Trypsin is used as positive control. Negative controls contain only alpha-2-macroglobulin in assay buffer. The samples are collected and boiled in SDS-PAGE sample buffer containing 5% 2-mercaptoethanol for 5-min, then loaded onto 8% SDS-polyacrylamide gel. After electrophoresis the proteins are visualized by silver staining. Proteolysis is evident by the appearance of lower molecular weight bands as compared to the negative control.

Inhibition of Alpha-2-Macroglobulin Proteolysis by Inhibitors of Metalloproteinases

Known metalloproteinase inhibitors (metal chelators (EDTA, EGTA, AND HgCl₂), peptide metalloproteinase inhibitors (TIMP-1 and TIMP-2), and commercial small molecule MMP inhibitors) are used to characterize the proteolytic activity of polypeptides of the invention. The three synthetic MMP inhibitors used are: MMP inhibitor I, [IC₅₀=1.0 μM against MMP-1 and MMP-8; IC₅₀=30 μM against MMP-9; IC₅₀=150 μM against MMP-3]; MMP-3 (stromelysin-1) inhibitor I [IC₅₀=5 μM against MMP-3], and MMP-3 inhibitor II [K_(i)=130 nM against MMP-3]; inhibitors available through Calbiochem, catalog # 444250, 444218, and 444225, respectively). Briefly, different concentrations of the small molecule NMP inhibitors are mixed with purified polypeptides of the invention (50 μg/ml) in 22.9 μl of 1×HEPES buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl, 10 mM CaCl₂, 25 μM ZnCl₂ and 0.05% Brij-35) and incubated at room temperature (24° C.) for 2-hr, then 7.1 μl of substrate alpha-2-macroglobulin (0.2 unit/ml) is added and incubated at 37° C. for 20-hr. The reactions are stopped by adding 4× sample buffer and boiled immediately for 5 minutes. After SDS-PAGE, the protein bands are visualized by silver stain.

Synthetic Fluorogenic Peptide Substrates Cleavage Assay

The substrate specificity for polypeptides of the invention with demonstrated metalloproteinase activity can be determined using synthetic fluorogenic peptide substrates purchased from BACHEM Bioscience Inc). Test substrates include, M-1985, M-2225, M-2105, M-2110, and M-2255. The first four are MMP substrates and the last one is a substrate of tumor necrosis factor-α (TNF-α) converting enzyme (TACE). All the substrates are prepared in 1:1 dimethyl sulfoxide (DMSO) and water. The stock solutions are 50-500 μM. Fluorescent assays are performed by using a Perkin Elmer LS 50B luminescence spectrometer equipped with a constant temperature water bath. The excitation λ is 328 nm and the emission λ is 393 nm. Briefly, the assay is carried out by incubating 176 μl 1×HEPES buffer (0.2 M NaCl, 10 mM CaCl₂, 0.05% Brij-35 and 50 mM HEPES, pH 7.5) with 4 μl of substrate solution (50 μM) at 25° C. for 15 minutes, and then adding 20 μl of a purified polypeptide of the invention into the assay cuvett. The final concentration of substrate is 1 μM. Initial hydrolysis rates are monitored for 30-min.

Example 61 Characterization of the cDNA Contained in a Deposited Plasmid

The size of the cDNA insert contained in a deposited plasmid may be routinely determined using techniques known in the art, such as PCR amplification using synthetic primers hybridizable to the 3′ and 5′ ends of the cDNA sequence. For example, two primers of 17-30 nucleotides derived from each end of the cDNA (i.e., hybridizable to the absolute 5′ nucleotide or the 3′ nucleotide end of the sequence of SEQ ID NO:X, respectively) are synthesized and used to amplify the cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 25 ul of reaction mixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-5 mM MgCl₂, 0.01% (w/v) gelatin, 20 uM each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturation at 94 degree C. for 1 min; annealing at 55 degree C. for 1 min; elongation at 72 degree C. for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis. The PCR product is verified to be the selected sequence by subcloning and sequencing the DNA product. It will be clear that the invention may be practiced otherwise than as particularly described in the foregoing description and examples. Numerous modifications and variations of the present invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims.

Incorporation by Reference

The entire disclosure of each document cited (including patents, patent applications, journal articles, abstracts, laboratory manuals, books, or other disclosures) in the Background of the Invention, Detailed Description, and Examples is hereby incorporated herein by reference. In addition, the sequence listing submitted herewith is incorporated herein by reference in its entirety. The specification and sequence listing of each of the following U.S. and PCr applications are herein incorporated by reference in their entirety (filing dates shown in format “year-month-day” (yyyy-mm-dd)): Application No. 60/278,650 filed on 2001-03-27, application Ser. No. 09/950,082 filed on 2001-09-12, application Ser. No. 09/950,083 filed on 2001-09-12, Application No. 60/306,171 filed on 19-Jul.-2001, application Ser. No. 09/833,245 filed on 2001-04-12, Application No. PCT/US01/11988 filed on 2001-04-12, Application No. 60/331,287 filed on 2001-11-13, Application No. 60/277,340 filed on 2001-03-21, Application No. PCT/US00/06043 filed on 2000-03-09, Application No. PCT/US00/06012 filed on 2000-03-09, Application No. PCT/US00/06058 filed on 2000-03-09, Application No. PCT/US00/06044 filed on 2000-03-09, Application No. PCT/US/00/06059 filed on 2000-03-09, Application No. PCT/US00/06042 filed on 2000-03-09, Application No. PCT/US00/06014 filed on 2000-03-09, Application No. PCT/US00/06013 filed on 2000-03-09, Application No. PCT/US00/06049 filed on 20004-03-09, Application No. PCT/US00/06057 filed on 2000-03-09, Application No. PCT/US00/06824 filed on 2000-03-16, Application No. PCT/US00/06765 filed on 2000-03-16, Application No. PCT/US00/06792 filed on 2000-03-16, Application No. PCT/US00/06830 filed on 2000-03-16, Application No. PCT/US00/06782 filed on 2000-03-16, Application No. PCT/US00/06822 filed on 2000-03-16, Application No. PCT/US00/06791 filed on 2000-03-16, Application No. PCT/US00/06828 filed on 2000-03-16, Application No. PCT/US00/06823 filed on 2000-03-16, Application No. PCT/US00/06781 filed on 2000-03-16, Application No. PCT/US00/07505 filed on 2000-03-22, Application No. PCT/US00/07440 filed on 2000-03-22, Application No. PCT/US00/07506 filed on 2000-03-22, Application No. PCT/US00/07507 filed on 2000-03-22, Application No. PCT/US00/07535 filed on 2000-03-22, Application No. PCT/US00/07525 filed on 2000-03-22, Application No. PCT/US00/07534 filed on 2000-03-22, Application No. PCT/US00/07483 filed on 2000-03-22, Application No. PCT/US00/07526 filed on 2000-03-22, Application No. PCT/US00/07527 filed on 2000-03-22, Application No. PCT/US00/07661 filed on 2000-03-23, Application No. PCT/US00/07579 filed on 2000-03-23, Application No. PCT/US00/07723 filed on 2000-03-23, Application No. PCT/US00/07724 fled on 2000-03-23, Application No. PCT/US00/14929 filed on 2000-06-01, Application No. PCT/US00/07722 filed on 2000-03-23, Application No. PCT/US00/07578 filed on 2000-03-23, Application No. PCT/US00/07726 filed on 2000-03-23, Application No. PCT/US00/07677 filed on 2000-03-23, Application No. PCT/US00/07725 filed on 2000-03-23, Application No. PCT/US00/09070 filed on 2000-04-06, Application No. PCT/US00/08982 filed on 2000-04-06, Application No. PCT/US00/08983 filed on 2000404-06, Application No. PCT/US00/09067 filed on 2000-046, Application No. PCT/US00/09066 filed on 2000404-06, Application No. PCT/US00/09068 filed on 2000-04-06, Application No. PCT/US00/08981 fled on 2000-04-06, Application No. PCT/US00/08980 filed on 2000-04-06, Application No. PCT/US00/09071 fled on 2000-04-06, Application No. PCT/US00/09069 filed on 2000-04-06, Application No. PCT/US00/15136 filed on 2000-06-01, Application No. PCT/US00/14926 filed on 2000-06-01, Application No. PCT/US00/14963 filed on 2000-06-01, Application No. PCT/US00/15135 filed on 2000-06-01, Application No. PCT/US00/14934 filed on 2000-06-01, Application No. PCT/US00/14933 filed on 2000-06-01, Application No. PCT/US00/15137 filed on 2000-04-06, Application No. PCT/US00/14928 filed on 2000-06-01, Application No. PCT/US00/14973 filed on 2000-06-01, Application No. PCT/US00/14964 filed on 2000-06-01, Application No. PCT/US00/26376 filed on 2000-09-26, Application No. PCT/US00/26371 filed on 2000-09-26, Application No. PCT/US00/26324 filed on 2000-09-26, Application No. PCT/US00/26323 filed on 2000-09-26, Application No. PCT/US00/26337 filed on 2000-09-26, Application No. PCT/US01/13318 filed on 2001-04-27, Application No. U.S. 60/124,146 filed on 1999-03-12, Application No. U.S. 60/167,061 filed on 1999-11-23, Application No. U.S. 60/124,093 filed on 1999-03-12, Application No. U.S. 60/166,989 filed on 1999-11-23, Application No. U.S. 60/124,145 filed on 1999-03-12, Application No. U.S. 60/168,654 filed on 1999-12-03, Application No. U.S. 60/124,099 filed on 1999-03-12, Application No. U.S. 60/168,661 filed on 1999-12-03, Application No. U.S. 60/124,096 filed on 1999-03-12, Application No. U.S. 60/168,622 filed on 1999-12-03, Application No. U.S. 60/124,143 filed on 1999-03-12, Application No. U.S. 60/168,663 filed on 1999-12-03, Application No. U.S. 60/124,095 filed on 1999-03-12, Application No. U.S. 60/138,598 filed on 1999-06-11, Application No. U.S. 60/168,665 filed on 1999-12-03, Application No. U.S. 60/125,360 filed on 1999-03-19, Application No. U.S. 60/138,626 filed on 1999-06-11, Application No. U.S. 60/168,662 filed on 1999-12-03, Application No. U.S. 60/124,144 filed on 1999-03-12, Application No. U.S. 60/138,574 filed on 1999-06-11, Application No. U.S. 60/168,667 filed on 1999-12-03, Application No. U.S. 60/124,142 filed on 1999-03-12, Application No. U.S. 60/138,597 filed on 1999-06-11, Application No. U.S. 60/168,666 filed on 1999-12-03, Application No. U.S. 60/125,359 filed on 1999-03-19, Application No. U.S. 60/168,664 filed on 1999-12-03, Application No. U.S. 60/126,051 filed on 1999-03-23, Application No. U.S. 60/169,906 filed on 1999-12-10, Application No. U.S. 60/125,362 filed on 1999-03-19, Application No. U.S. 60/169,980 filed on 1999-12-10, Application No. U.S. 60/125,361 filed on 1999-03-19, Application No. U.S. 60/169,910 filed on 1999-12-10, Application No. U.S. 60/125,812 filed on 1999-03-23, Application No. U.S. 60/169,936 filed on 1999-12-10, Application No. U.S. 60/126,054 filed on 1999-03-23, Application No. U.S. 60/169,916 filed on 1999-12-10, Application No. U.S. 60/125,815 filed on 1999-03-23, Application No. U.S. 60/169,946 filed on 1999-12-10, Application No. U.S. 60/125,358 filed on 1999-03-19, Application No. U.S. 60/169,616 filed on 1999-12-08, Application No. U.S. 60/125,364 filed on 1999-03-19, Application No. U.S. 60/169,623 filed on 1999-12-08, Application No. U.S. 60/125,363 filed on 1999-03-19, Application No. U.S. 60/169,617 filed on 1999-12-08, Application No. U.S. 60/126,502 filed on 1999-03-26, Application No. U.S. 60/172,410 filed on 1999-12-17, Application No. U.S. 60/126,503 filed on 1999-03-26, Application No. U.S. 60/172,409 filed on 1999-12-17, Application No. U.S. 60/126,505 filed on 1999-03-26, Application No. U.S. 60/172,412 filed on 1999-12-17, Application No. U.S. 60/126,594 filed on 1999-03-26, Application No. U.S. 60/172,408 filed on 1999-12-17, Application No. U.S. 60/126,511 filed on 1999-03-26, Application No. U.S. 60/172,413 filed on 1999-12-17, Application No. U.S. 60/126,595 filed on 1999-03-26, Application No. U.S. 60/171,549 filed on 1999-12-22, Application No. U.S. 60/126,598 filed on 1999-03-26, Application No. U.S. 60/171,504 filed on 1999-12-22, Application No. U.S. 60/126,596 filed on 1999-03-26, Application No. U.S. 60/171,552 filed on 1999-12-22, Application No. U.S. 60/126,600 filed on 1999-03-26, Application No. U.S. 60/171,550 filed on 1999-12-22, Application No. U.S. 60/126,501 filed on 1999-03-26, Application No. U.S. 60/171,551 filed on 1999-12-22, Application No. U.S. 60/126,504 filed on 1999-03-26, Application No. U.S. 60/174,847 filed on 2000-01-07, Application No. U.S. 60/126,509 filed on 1999-03-26, Application No. U.S. 60/174,853 filed on 2000-01-07, Application No. U.S. 60/126,506 filed on 1999-03-26, Application No. U.S. 60/174,852 filed on 2000-01-07, Application No. U.S. 60/242,710 filed on 2000-10-25, Application No. U.S. 60/126,510 filed on 1999-03-26, Application No. U.S. 60/174,850 filed on 2000-01-07, Application No. U.S. 60/138,573 filed on 1999-06-11, Application No. U.S. 60/174,851 filed on 2000-01-07, Application No. U.S. 60/126,508 filed on 1999-03-26, Application No. U.S. 60/174,871 filed on 2000-01-07, Application No. U.S. 60/126,507 filed on 1999-03-26, Application No. U.S. 60/174,872 filed on 2000-01-07, Application No. U.S. 60/126,597 filed on 1999-03-26, Application No. U.S. 60/174,877 filed on 2000-01-07, Application No. U.S. 60/126,601 filed on 1999-03-26, Application No. U.S. 60/154,373 filed on 1999-09-17, Application No. U.S. 60/176,064 filed on 2000-01-14, Application No. U.S. 60/126,602 filed on 1999-03-26, Application No. U.S. 60/176,063 filed on 2000-01-14, Application No. U.S. 60/128,695 filed on 1999-04-09, Application No. U.S. 60/176,052 filed on 2000-01-14, Application No. U.S. 60/128,696 filed on 1999-04-09, Application No. U.S. 60/176,069 filed on 2000-01-14, Application No. U.S. 60/128,703 filed on 1999-04-09, Application No. U.S. 60/176,068 filed on 2000-01-14, Application No. U.S. 60/128,697 filed on 199909, Application No. U.S. 60/176,929 filed on 2000-01-20, Application No. U.S. 60/128,698 filed on 199909, Application No. U.S. 60/176,926 filed on 2000-01-20, Application No. U.S. 60/128,699 filed on 1999-04-09, Application No. U.S. 60/177,050 filed on 2000-01-20, Application No. U.S. 60/128,701 filed on 1999-04-09, Application No. U.S. 60/177,166 filed on 2000-01-20, Application No. U.S. 60/128,700 filed on 1999-09, Application No. U.S. 60/176,930 filed on 2000-01-20, Application No. U.S. 60/128,694 filed on 1999-04-09, Application No. U.S. 60/176,931 filed on 2000-01-20, Application No. U.S. 60/128,702 filed on 1999-04-09, Application No. U.S. 60/177,049 filed on 2000-01-20, Application No. U.S. 60/138,629 filed on 1999-06-11, Application No. U.S. 60/138,628 filed on 1999-06-11, Application No. U.S. 60/138,631 filed on 1999-06-11, Application No. U.S. 60/138,632 filed on 1999-06-11, Application No. U.S. 60/138,599 filed on 1999-06-11, Application No. U.S. 60/138,572 filed on 1999-06-11, Application No. U.S. 60/138,625 filed on 1999-06-11, Application No. U.S. 60/138,633 filed on 1999-06-11, Application No. U.S. 60/138,630 filed on 1999-06-11, Application No. U.S. 60/138,627 filed on 1999-06-11, Application No. U.S. 60/155,808 filed on 1999-09-27, Application No. U.S. 60/155,804 filed on 1999-09-27, Application No. U.S. 60/155,807 filed on 1999-09-27, Application No. U.S. 60/155,805 filed on 1999-09-27, Application No. U.S. 60/155,806 filed on 1999-09-27, Application No. U.S. 60/201,194 filed on 2000-05-O₂, and Application No. U.S. 60/212,142 filed on 2000-06-16.

Europe

In respect of those designations in which a European Patent is sought a sample of the deposited microorganism will be made available until the publication of the mention of the grant of the European patent or until the date on which the application has been refused or withdrawn or is deemed to be withdrawn, only by the issue of such a sample to an expert nominated by the person requesting the sample (Rule 28(4) EPC).

Canada

The applicant requests that, until either a Canadian patent has been issued on the basis of an application or the application has been refused, or is abandoned and no longer subject to reinstatement, or is withdrawn, the Commissioner of Patents only authorizes the furnishing of a sample of the deposited biological material referred to in the application to an independent expert nominated by the Commissioner, the applicant must, by a written statement, inform the International Bureau accordingly before completion of technical preparations for publication of the international application.

Norway

The applicant hereby requests that the application has been laid open to public inspection (by the Norwegian Patent Office), or has been finally decided upon by the Norwegian Patent Office without having been laid open inspection, the furnishing of a sample shall only be effected to an expert in the art. The request to this effect shall be filed by the applicant with the Norwegian Patent Office not later than at the time when the application is made available to the public under Sections 22 and 33(3) of the Norwegian Patents Act. If such a request has been filed by the applicant, any request made by a third party for the furnishing of a sample shall indicate the expert to be used. That expert may be any person entered on the list of recognized experts drawn up by the Norwegian Patent Office or any person approved by the applicant in the individual case.

Australia

The applicant hereby gives notice that the furnishing of a sample of a microorganism shall only be effected prior to the grant of a patent, or prior to the lapsing, refusal or withdrawal of the application, to a person who is a skilled addressee without an interest in the invention (Regulation 3.25(3) of the Australian Patents Regulations).

Finland

The applicant hereby requests that, until the application has been laid open to public inspection (by the National Board of Patents and Regulations), or has been finally decided upon by the National Board of Patents and Registration without having been laid open to public inspection, the furnishing of a sample shall only be effected to an expert in the art.

United Kingdom

The applicant hereby requests that the furnishing of a sample of a microorganism shall only be made available to an expert. The request to this effect must be filed by the applicant with the International Bureau before the completion of the technical preparations for the international publication of the application.

Denmark

The applicant hereby requests that, until the application has been laid open to public inspection (by the Danish Patent Office), or has been finally decided upon by the Danish Patent office without having been laid open to public inspection, the furnishing of a sample shall only be effected to an expert in the art. The request to this effect shall be filed by the applicant with the Danish Patent Office not later that at the time when the application is made available to the public under Sections 22 and 33(3) of the Danish Patents Act. If such a request has been filed by the applicant, any request made by a third party for the furnishing of a sample shall indicate the expert to be used. That expert may be any person entered on a list of recognized experts drawn up by the Danish Patent Office or any person by the applicant in the individual case.

Sweden

The applicant hereby requests that, until the application has been laid open to public inspection (by the Swedish Patent Office), or has been finally decided upon by the Swedish Patent Office without having been laid open to public inspection, the furnishing of a sample shall only be effected to an expert in the art. The request to this effect shall be filed by the applicant with the International Bureau before the expiration of 16 months from the priority date (preferably on the Form PCT/RO/134 reproduced in annex Z of Volume I of the PCT Applicant's Guide). If such a request has been filed by the applicant any request made by a third party for the furnishing of a sample shall indicate the expert to be used. That expert may be any person entered on a list of recognized experts drawn up by the Swedish Patent Office or any person approved by a applicant in the individual case.

Netherlands

The applicant hereby requests that until the date of a grant of a Netherlands patent or until the date on which the application is refused or withdrawn or lapsed, the microorganism shall be made available as provided in the 31F(1) of the Patent Rules only by the issue of a sample to an expert. The request to this effect must be furnished by the applicant with the Netherlands Industrial Property Office before the date on which the application is made available to the public under Section 22C or Section 25 of the Patents Act of the Kingdom of the Netherlands, whichever of the two dates occurs earlier. LENGTHY TABLE The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070026454A1) An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3). 

1-32. (canceled)
 33. An isolated nucleic acid molecule comprising a first polynucleotide sequence at least 95% identical to a second polynucleotide sequence selected from the group consisting of: (a) a polynucleotide fragment of SEQ ID NO:X as referenced in Table 1A; (b) a polynucleotide encoding a full length polypeptide of SEQ ID NO:Y or a full length polypeptide encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (c) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (d) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A, wherein said fragment has biological activity; (e) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y as referenced in Table 1B; (f) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y as referenced in Table 2; (g) a polynucleotide encoding a predicted epitope of SEQ ID NO:Y as referenced in Table 1B; and (h) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(g), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.
 34. The isolated nucleic acid molecule of claim 33, wherein the polynucleotide fragment comprises a nucleotide sequence encoding a secreted form of SEQ ID NO:Y or a secreted form of the polypeptide encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y, as referenced in Table 1A.
 35. The isolated nucleic acid molecule of claim 33, wherein the polynucleotide fragment comprises a nucleotide sequence encoding the sequence identified as SEQ ID NO:Y or the polypeptide encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X, as referenced in Table 1A.
 36. The isolated nucleic acid molecule of claim 33, wherein the polynucleotide fragment comprises the entire nucleotide sequence of SEQ ID NO:X or the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X, as referenced in Table 1A.
 37. The isolated nucleic acid molecule of claim 34, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.
 38. The isolated nucleic acid molecule of claim 35, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.
 39. A recombinant vector comprising the isolated nucleic acid molecule of claim
 33. 40. A method of making a recombinant host cell comprising the isolated nucleic acid molecule of claim
 33. 41. A recombinant host cell produced by the method of claim
 40. 42. The recombinant host cell of claim 41 comprising vector sequences.
 43. A polypeptide comprising a first amino acid sequence at least 95% identical to a second amino acid sequence selected from the group consisting of: (a) a full length polypeptide of SEQ ID NO:Y or a full length polypeptide encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (b) a secreted form of SEQ ID NO:Y or a secreted form of the polypeptide encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (c) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (d) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A, wherein said fragment has biological activity; (e) a polypeptide domain of SEQ ID NO:Y as referenced in Table 1B; (f) a polypeptide domain of SEQ ID NO:Y as referenced in Table 2; and (g) a predicted epitope of SEQ ID NO:Y as referenced in Table 1B.
 44. The polypeptide of claim 43, wherein said polypeptide comprises a heterologous amino acid sequence.
 45. The isolated polypeptide of claim 43, wherein the secreted form or the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.
 46. An isolated antibody that binds specifically to the isolated polypeptide of claim
 43. 47. A recombinant host cell that expresses the isolated polypeptide of claim
 43. 48. A method of making an isolated polypeptide comprising: (a) culturing the recombinant host cell of claim 47 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.
 49. The polypeptide produced by claim
 48. 50. A method for preventing, treating, or ameliorating a hematopoietic or hematologic disorder, comprising administering to a mammalian subject a therapeutically effective amount of the polypeptide of claim
 43. 51. A method of diagnosing a hematopoietic or hematologic disorder in a subject comprising: (a) determining the presence or absence of a mutation in the polynucleotide of claim 33; and (b) diagnosing the hematopoietic or hematologic disorder based on the presence or absence of said mutation.
 52. A method of diagnosing a hematopoietic or hematologic disorder in a subject comprising: (a) determining the presence or amount of expression of the polypeptide of claim 43 in a biological sample; and (b) diagnosing the hematopoietic or hematologic disorder based on the presence or amount of expression of the polypeptide.
 53. A method for identifying a binding partner to the polypeptide of claim 43 comprising: (a) contacting the polypeptide of claim 43 with a binding partner; and (b) determining whether the binding partner effects an activity of the polypeptide.
 54. The gene corresponding to the cDNA sequence of SEQ ID NO:X.
 55. A method of identifying an activity in a biological assay, wherein the method comprises: (a) expressing SEQ ID NO:X in a cell; (b) isolating the supernatant; (c) detecting an activity in a biological assay; and (d) identifying the protein in the supernatant having the activity.
 56. The product produced by the method of claim
 53. 